Arterial stiffness index (ASI) is closely related to coronary atherosclerosis. This study aims to explore whether ASI can predict coronary heart disease (CHD) and its severity.In this study, a total of 726 patients with suspected CHD were recruited. Based on coronary angiography results, the subjects were assigned into three groups: the control group (without obvious coronary artery disease), single-vessel disease group, and multi-vessel disease group (the number of vessels diseased ≥ 2). At the same time, according to the results of angiography, myocardial enzyme spectrum, electrocardiogram, color Doppler echocardiography and clinical manifestations, these patients were divided into four groups: the control group, stable angina (SA) Group, unstable angina (UA) group, and acute myocardial infarction (AMI) group. We have compared whether there were differences in ASI and related baseline data between groups. Receiver operating curve (ROC) analysis was conducted to determine whether ASI could predict CHD and evaluate the severity.ASI was positively correlated with the number of diseased branches of coronary artery. The value of ASI was increased as the number of the diseased branches increased. The ASI value in the SA group was significantly higher compared with the control group. Furthermore, the ASI value in the UA and AMI groups was remarkably increased compared with the control and SA groups. The results of ROC analysis indicated that the sensitivity and specificity of ASI was 71.0% and 85.4% in diagnosing CHD, respectively. While ASI was used in predicting the severity of CHD, the sensitivity was 72.1% and specificity 57.9%.ASI is of great value in the diagnosis of coronary heart disease and the prediction of its severity. Cardiovascular disease, especially CHD, is one of the important diseases affecting life and health. Although accumulating research has investigated the disease in the past, numerous related issues on diagnosis, treatment and prognosis remained to be resolved . CHD is Arteriosclerosis is an independent risk factor of CHD and other cardiovascular diseases , 3. In rBased on previous studies, detecting ASI could predict CHD and evaluate its severity. This can provide new reference for the diagnosis and treatment of CHD in the future.We selected 933 patients with suspected CHD who were hospitalized in the Department of Cardiology, Affiliated Hospital of Yangzhou University from January 2019 to December 2020, finally, 726 patients were selected. Among these patients, patients with AMI mainly come from emergency department, and other patients mainly come from cardiology outpatient department. The exclusion criteria are as follows: 1. Severe liver, kidney and pancreatic diseases; 2. Chronic wasting diseases and malignant tumors; 3. Frequent ectopic arrhythmias; 4. Those who do not cooperate with the inspection. All the subjects underwent coronary angiography based on the requirements of the American Heart College (ACC)/American Heart Association (AHA) coronary angiography guidelines. We mainly observed the lesions of left anterior descending (LAD) branch, left circumflex (LCX) branch, right coronary artery (RCA) and their main branches . AccordiRelated risk factors such as gender, weight, age, smoking history, diabetes history, hypertension history, etc. were obtained from all the subjects through questionnaire surveys according to protocols .Venous blood samples were obtained in the early morning after admission. By using the fully automatic biochemical analyser , related blood biochemical indicators were detected, including cholesterol , triglycerides , high-density lipoprotein cholesterol , low-density cholesterol lipoprotein , lipoprotein(a), uric acid , etc. All tests were performed at the Clinical Laboratory Center of the Affiliated Hospital of Yangzhou University. The laboratory quality control standards were met in this test.Basic principles Our study was to record the pressure shock wave when blood pressure was measured by oscillometry with an arterial meter. In the process of blood pressure measurement, the inflation pressure in the cuff gradually decreased after reaching the predetermined maximum value, and the arterial blood flow pressure wave detected in the cuff showed regular changes. When the cuff pressure was higher than the systolic pressure, the brachial artery blood flow was completely blocked. The brachial artery above the cuff expanded due to cardiac contraction, so the cuff pressure showed small fluctuations. When the cuff pressure was lower than the systolic pressure, with the gradual opening of the brachial artery below the cuff, the blood flow increased gradually, and the cuff pressure fluctuation amplitude recorded also increased gradually. When the cuff pressure was equal to the average pressure, the pressure fluctuation in the cuff reached the maximum. After that, the cuff pressure decreased gradually, and the pressure fluctuation decreased accordingly. When the cuff pressure was equal to the diastolic pressure, the pressure fluctuation amplitude decreased significantly. After that, as the blood flow was completely unblocked, and the pressure fluctuation amplitude in the cuff tensed to be stable. The ASI value was defined as the width value of the pressure fluctuation diagram corresponding to 80% of the peak height of the maximum pressure wave multiplied by 10, We also designed the basic schematic diagram, as shown in Fig. Measurement method The subject was required to rest at least 15 min before the measurement. During the measurement, the subject took a seated position with the cuff placed on about 5 cm above the elbow joint of the right upper limb. The maximum inflation pressure of the air cuff (maximum pressure was 300 mmHg) was dependent on the blood pressure of the subjects. When the internal pressure of the cuff reached the maximum inflation pressure, inflation was automatically stopped. Then the cuff automatically deflated at a constant rate. After deflation, ASI, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure and heart rate could be automatically displayed. During the measurement, the subject kept normal breathing with the whole body relaxed, and avoided moving arms. The measurement was repeated for 3 times to obtain the average value. The time interval between adjacent measurements was more than 5 min. Japanese CardioVision MS-2000 arterial stiffness measuring instrument was used in this experiment.Medcalc software was used to draw the ROC. The area under the curve (AUC) was compared and the cut-off value of ASI evaluated, which were used to determine the occurrence and severity of CHD. The severity of CHD was mainly judged by comparing single-vessel lesions with multiple-vessel lesions.P value was two-sided, and P ≤ 0.05 was considered statistically significant.In this study, SPSS 22.0  statistical software package was used for data analysis. For the data conforming to the normal distribution, mean ± standard deviation was used. One-way analysis of variance or independent sample t test was applied to compare the differences between groups. The chi-square test was used in analyzing the proportional data. For the data not conforming to the normal distribution, the median and interquartile range was used. Univariate and multivariate regression analysis was used to evaluate the relationship between the severity of CHD and ASI value. The A total of 726 patients participated in the study. All patients underwent coronary angiography. According to the results of the examinations, 562 participants were diagnosed with CHD (at least one vessel with vasculopathy degree ≥ 50%), while the other 164 patients were regarded as control group (no one vessel with vasculopathy degree ≥ 50%). Among patients with CHD, there were 340 patients in the single-vessel disease group and 222 patients in the multi-vessel disease group. According to the severity of clinical manifestations, among patients with CHD, there were 164 patients suffered from stable angina, 236 patients unstable angina and 162 patients with acute myocardial infarction.P < 0.05).As shown in Table P < 0.05).According to the severity of clinical manifestations, all the participants were assigned into four groups Table . CompareROC analysis was used to determine the role of ASI in diagnosing CHD and assessing its severity Fig. . The areCoronary arteriosclerosis is one of the important causes of CHD , and bloAs is known to all, vascular endothelial cells can synthesize and release a variety of vasoactive substances, which play a vital role in maintaining vascular functions, such as vasodilation, inhibition of platelet adhesion, and the proliferation of vascular smooth muscle cell , 15. PreReduced vascular compliance resulted from endothelial dysfunction generally occurs earlier than atherosclerotic plaque formation, which is the earliest manifestation of vasculopathy , 19. TheOur study was the first research using ROC analysis to determine the diagnostic value of ASI for CHD. The results of ROC analysis showed that ASI could not only serve a part in the predictive diagnosis of CHD, but also played a pivotal role in assessing the severity of CHD. Higher ASI value indicated that CHD was more serious. There are also some limitations in our research. First of all, our research time was relatively short and the number of cases was relatively small. Secondly, we have not performed vascular endothelial cell function test, which may require further validation in future animal experiments. Finally, for some patients with microvascular disease , their test results might have some impact on our research, however, we believed that these impacts were limited.In short, as one of the indicators reflecting vascular compliance, ASI closely related to the severity of CHD. Our research results demonstrated that ASI could provide a new basis for predicting and diagnosing CHD, which also could provides a new idea for the prevention and treatment of CHD in the future.


Acute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support.2) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70–80 mmHg. Intra-group differences were tested by Mann–Whitney U-tests, and a linear mixed model was used to test time and group interaction.In this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvOp = 0.030), and the estimated GFR was lower . Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance . There was a trend for a minor increase in glomerular filtration rate with levosimendan , which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012).Twenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, In hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1NCT02531724, prospectly registered on 08/20/2015.  Acute kidney injury (AKI) is a common complication after cardiac surgery and associated with increased morbidity and mortality . Even miIn AKI, the deterioration of renal excretory function, i.e., a reduction of the glomerular filtration rate (GFR), leads to retention of nitrogen metabolism waste products, detectable as an increased serum creatinine concentration. Thus, a reasonable goal in the management of AKI would be to improve the GFR. As there is a close relationship between GFR, tubular sodium reabsorption and renal oxygen consumption –7, a druLevosimendan is a calcium sensitizing agent used as an inodilator in cardiac failure. Although three major trials have failed to demonstrate a superiority of levosimendan over placebo regarding prevention of major adverse outcomes after cardiac surgery such as acute kidney injury –11, otheTo test the hypothesis that levosimendan improves renal function in patients with postoperative AKI who do not otherwise require inotropic support, we performed a blinded randomized placebo-controlled trial. Our aim was to test the effect of a short-term infusion of levosimendan on RBF and GFR. Our hypothesis was that infusion of levosimendan in early cardiac surgery-associated AKI increases both RBF and GFR.2) < 60%, (3) impaired RBF due to vascular obstruction, e.g., from a dissection membrane. All patients were studied at the cardiothoracic intensive care unit at Sahlgrenska University Hospital, Gothenburg, Sweden. Written informed consent was obtained from all participants, or a next of kin, before initiation of the study protocol.The study protocol was approved by the regional Ethics Committee in Gothenburg, Sweden, , and registered in ClinicalTrials.gov  preoperative serum creatinine levels within the normal range . (2) postoperative acute kidney injury, defined as a postoperative increase (within 48 h) in serum creatinine of ≥ 27 mmol or an increase of > 50%, according to the KDIGO criteria, (3) written informed consent, (4) age > 18 years old, (5) postoperative care after open cardiac surgery with CPB. Exclusion criteria were: (1) ongoing treatment with inotropic medication (except for norepinephrine), (2) central venous saturation  to placebo or levosimendan. The randomization was stratified for gender, mechanical ventilation (yes/no), and preoperative left ventricle ejection fraction above or below 50%. A nurse, not otherwise involved in the treatment of the patient, randomized the patients and prepared the study-drug. To ensure blinding, considering that levosimendan has a yellow tint, the study drug was administered with opaque syringes and tubing, and the same volume and infusion rate was used in both the placebo and the levosimendan group.During the study, measurements, as described below, were made before (baseline) and during treatment. The baseline value was the average of two measurements at 30 min interval before study drug administration, and the treatment measurements were the averages of three different time points, made at 3, 4 and 5 h after the start of the study drug infusion. Patients randomized to levosimendan  were given a bolus infusion (12 µg/kg) over 30 min, followed by 0.1 µg/kg/min for 5 h. Patients randomized to placebo received acetated Ringer’s solution (Ringers-acetate Baxter Viaflo®) infused in the same volumes and infusion rates as in the levosimendan group. During the study period, any ongoing diuretic therapy was unchanged. Norepinephrine was administered to keep the blood pressure in the target mean arterial pressure (MAP) between 70 and 80 mmHg.2) and central venous (ScvO2) oxygen saturation and hematocrit. The norepinephrine dose and inspired oxygen levels were recorded. Renal perfusion pressure was calculated as MAP-CVP.The measurements included MAP obtained from an arterial line , central venous pressure (CVP) obtained from a central venous catheter , heart rate, body temperature and urinary output. Blood gases from arterial and central venous catheters were analyzed for arterial (SaO51Cr-EDTA) or iohexol, and renal plasma flow (RPF) was measured using infusion-clearance of para-amino-hippurate (PAH), as described below. Due to halted hospital delivery of Cr-EDTA, iohexol was used to determine GFR from June 2019. After the collection of blood blanks, an intravenous priming dose of 51Cr-EDTA  or iohexol  and PAH  were administered, followed by infusion at a constant rate, individualized to body surface area and postoperative serum creatinine. Serum concentrations of PAH and 51Cr-EDTA activity were measured by a spectrophotometer  and a well counter , respectively. Iohexol concentration was measured by ion mass spectrometry . RPF was measured using the infusion clearance technique for para-aminohippurate (PAH) and was calculated as the amount of infused PAH divided by the arterial PAH concentration, corrected for an assumed PAH extraction of 0.70, as shown by Redfors et al. in patients with AKI after cardiac surgery [51Cr-EDTA or iohexol divided by arterial content of the substance, and filtration fraction (FF) was calculated as GFR/RPF. Renal vascular resistance (RVR) was calculated as (MAP–CVP)/RBF. Estimated GFR (eGFR) was calculated using the CKD-EPI Creatinine Equation [2.GFR was measured using infusion-clearance technique of chromium-ethylenediamine tetra acetic acid  was used for all statistical analyses.Based on the study by Bragadottir et al. , we estiBetween September 2015 and June 2020, 36 patients were screened. Two patients declined to participate, and four patients were excluded prior to randomization due to lack of time and bed space in the cardiothoracic ICU. One patient, randomized to placebo, did not finish the protocol due to hemodynamic instability and need for inotropic support, and was excluded from the analysis. In total, 29 patients were included in the study, see Consort flow diagram, Fig. p = 0.026). Betablocker treatment was more common in the placebo group (p = 0.020), but all other comorbidities and medications were comparable between the groups.Table p = 0.108). At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan , and the estimated GFR (eGFR) was lower . In the levosimendan group, five patients had AKI grade 2 at inclusion, all the remaining patients of both groups had AKI grade 1 (p = 0.048 between groups).The patients were included at 34 ± 14 and 24 ± 10 h after the end of CPB in the levosimendan and placebo group, respectively (p = 0.009), body temperature was slightly increased (p = 0.036) and erythrocyte volume fraction (EVF) was slightly reduced (p = 0.003) during treatment. In the levosimendan group, the treatment was accompanied by increased norepinephrine dose  and heart rate , while the other systemic variables remained unchanged. No new-onset atrial fibrillation or other arrhythmias were seen during the experimental procedure.Central hemodynamic parameters at baseline and during treatment are shown in Table p = 0.012). Otherwise, there were no significant differences between the two groups with respect to the evolution of systemic variables.When comparing the two groups, the norepinephrine dose was significantly higher in the levosimendan group compared to the placebo group . In the placebo group, none of the renal variables changed during the experimental procedure. In the levosimendan group, RBF was increased , and renal vascular resistance (RVR) was reduced  during treatment. Filtration fraction was reduced by 12% (p = 0.003), and there was a trend towards increased GFR  after levosimendan treatment.Renal variables at baseline and treatment are shown in Table p = 0.011) and decreased RVR (p = 0.043). No group differences in GFR or other renal variables were found. In both groups, the mean serum creatinine was lower on the day after the study compared to on the inclusion, with no significant difference between the groups (p = 0.507). In patients with AKI grade 2 , there was a mean increase in serum creatinine on the first day after the study compared to inclusion .Compared to the placebo group, levosimendan increased RBF  towards increased GFR with levosimendan, but the increase was modest and thus of uncertain clinical significance, and there was no significant change in diuresis.To our knowledge, this is the first report on the specific renal effects of levosimendan in patients with AKI. The renal effects of levosimendan have previously studied in patients with normal renal function after cardiac surgery , in patiThere may be several reasons for this disparity regarding levosimendan-induced changes in GFR after cardiac surgery, as seen in the present study compared to the study of Bragadottir et al. . FirstlyRenal oxygenation is determined by the balance of renal oxygen consumption and delivery. The oxygen consumption increases with increased tubular sodium load, which is closely linked to GFR , 23. SinTwo major outcome studies, the LICORN  and LEVOThis study has some limitations. Most importantly, it is a small study, and despite randomization, the patients in the levosimendan group had more severe AKI with lower GFR and RBF than the placebo group at inclusion, which complicates the interpretation of our results (see above). Secondly, since renal vein catheterization was not used, no data on renal oxygen consumption, renal oxygenation or individual data on renal extraction of PAH are available. The strengths of the study are that it was blinded, randomized and placebo-controlled, evaluating the renal effects of levosimendan in patients with AKI, particularly with the view that pharmacodynamic studies on renal function in AKI are almost lacking.In patients with AKI after cardiac surgery, levosimendan improved renal blood flow through renal vasodilation, but had little or no effect on GFR. The levosimendan-induced fall in renal filtration fraction suggests that levosimendan may have improved renal oxygenation. Further studies with emphasis on outcome are needed before levosimendan can be recommended for the treatment of acute kidney injury.


Glaucomatous optic neuropathies have been regarded as diseases caused by high intraocular pressure for a long time, despite the concept of vascular glaucoma dating back to von Graefe in 1854. Since then, a tremendous amount of knowledge about the ocular vasculature has been gained; cohort studies have established new vascular risk factors for glaucoma as well as identifying protective measures acting on blood vessels. The knowledge about the physiology and pathophysiology of the choroidal, retinal, as well as ciliary and episcleral circulation has also advanced. Only recently have novel drugs based on that knowledge been approved for clinical use, with more to follow. This review provides an overview of the current vascular concepts in glaucoma, ranging from novel pathogenesis insights to promising therapeutic approaches, covering the supply of the optic nerve head as well as the aqueous humor production and drainage system.  Glaucoma  refers to a group of diseases characterized by retinal ganglion cell atrophy with corresponding visual field defects. If unrecognized or untreated, glaucoma can lead to severe visual impairment. It is amongst the most frequent causes of blindness in industrialized countries . Elevated intraocular pressure (IOP) is the most important risk factor for glaucoma, and lowering it is the only proven treatment to date ,3,4,5. BThis review aims to provide an overview of selected vascular aspects in glaucoma, covering vascular risk factors in epidemiological studies as well as physiological aspects in animal models and abnormal vascular findings in glaucoma patients. Several cohort studies conducted in different populations have identified vascular risk factors for various aspects of glaucoma, but findings are inconsistent.Low ocular perfusion pressure  has been identified as a risk factor for OAG in the Los Angeles Latino Eye Study , the EgnA recent meta-analysis found a consistent association of low perfusion pressure and POAG but not NTG , even thAn important caveat is the heterogeneity of the blood pressure (BP)-related formulas used in different studies. A report by Barbosa-Breda et al. found differences of up to 100% for the obtained OPP values depending on the applied formula . FurtherThe blood supply of the ocular tissues arises from the ophthalmic artery, the first major branch of the internal carotid artery, as it supplies the human orbit. The ocular branches of the ophthalmic artery can be divided into the central retinal artery and the posterior and anterior ciliary arteries . The cenAs in any tissue of the body, arterial blood pressure drives blood through the vasculature, and the combined resistance of all vessels causes a pressure drop at the venous side of the circulation . A major difference to most circulations, however, is the compressing force exerted by intraocular pressure (IOP). This causes the vortex veins to behave as Starling resistors, i.e., maintaining an intraluminal pressure slightly higher than IOP to prevent them from collapsing. Assuming that the venous pressure must be slightly higher than the intraocular pressure, the ocular perfusion pressure  is commonly approximated by the following formula :OPP = MAThis approximation, however, might not be accurate in clinically relevant pressure ranges. There is some evidence suggesting that the Starling resistor behavior outlined above may produce non-linear results, especially at low IOP values. Maepea was the first to note that choroidal venous pressure appears to be significantly higher than IOP at low IOP values .Currently, human in vivo measurements of retinal or choroidal venous pressure are technically not possible, despite approximations of retinal venous pressure existing with ophthalmodynamometry . UnpubliThe arteries of the choroid, retina, ciliary body, and optic nerve head circulations are all capable of active vascular resistance regulation, commonly termed autoregulation ,23,24,25The episcleral circulation is of high relevance for glaucoma because of its impact on intraocular pressure. Steady-state intraocular pressure (IOP) can be described by the Goldmann equation as the relationship between aqueous flow, uveoscleral outflow, outflow facility, and episcleral venous pressure (EVP) as an additive factor . EVP is The therapeutic potential of the episcleral circulation was recently confirmed in an experimental study with cromakalim prodrug 1 (CKLP1) in a mouse model. CKLP1 reduces EVP and thereby EVP–as predicted by the Goldmann equation. This effect is additive to other known substances acting on aqueous humor formation .Non-invasive measurement of ocular perfusion has been the focus of intense research interest in recent decades. A wide range of techniques all utilizing the Doppler effect have been introduced . The DopUltrasound-based color Doppler imaging is the only technology that measures the Doppler shifts in sound waves, whereas other techniques such as laser Doppler flowmetry, laser Doppler velocimetry, and Doppler optical coherence tomography use laser light see .Some of the techniques to measure perfusion of the ONH are limited to superficial tissue, supplied by the central retinal artery, but results from an animal model suggest that not only the superficial but also the deep ONH vascular supply is associated with pathologic changes in glaucoma . ContribThe laser speckle flowgraphy (LSFG) method is based on the laser speckle phenomenon. It describes an interference phenomenon occurring when a diffusing surface  is illuminated by a coherent light source . The backscattered light has the appearance of a granular pattern , which is entirely random and can only be described statistically . In the With color Doppler imaging, reduced blood flow velocities in retrobulbar vessels were shown in both high- and low-tension POAG patients compared with healthy control subjects ,48,49. TMuch attention has been given to the technology of OCT angiography . HoweverStudies reporting results from LSFG measurements in eyes with normal tension POAG have been published for over a decade. Significant differences in ONH perfusion have been shown between patients with normal tension glaucoma and healthy individuals ,57.All reported studies above were conducted as cross-sectional trials. Results of a prospective, longitudinal study on structure rather than perfusion, comparing healthy individuals with patients with preperimetric glaucoma and glaucoma patients with visual field defects, have indicated that macular vessel density measured with OCT angiography declined faster than the ganglion cell thickness . LongituUntil recently, only one longitudinal study reported changes in optic nerve head perfusion over time in humans. In 2005, Martínez et al. published results from a longitudinal trial where they observed 49 patients with high tension POAG over 36 months. In total, 23 eyes had progressed during the study period. The authors identified increased resistivity in the ophthalmic artery and the short posterior ciliary arteries as risk factors for the progression of glaucomatous visual field defects . In 2020Currently, there is no established therapy specifically addressing the choroidal or optic nerve head vasculature. Some IOP-lowering agents at least partly act through vasoconstriction in the ciliary body vasculature . One intFurthermore, the episcleral circulation recently emerged as a therapeutic target of new classes of IOP-lowering drugs as well as new routes of administration of existing drug classes.Rho-kinase inhibitors are a novel drug class for glaucoma treatment for which FDA approval was received in 2017 . They acAnother well-established drug class has an effect on the ocular vasculature. Prostaglandin analogs (PGAs) are an established drug class for glaucoma treatment , increasIn summary, both defining and treating possible vascular glaucoma triggers remain challenging in clinical routine as well as from a scientific point of view. Emerging technologies to measure ocular perfusion  in vivo have the potential to further elucidate the role of the ocular perfusion in the pathophysiology of glaucoma. Furthermore, current drug development utilizes obtained knowledge on the ocular vasculature and will likely be available in clinical practice soon.


Physiotherapy can include both device-guided slow breathing (DGSB) and nondevice-guided slow breathing (NDGSB) in the treatment of systemic arterial hypertension.The aim of this study is to summarize the effects of DGSB on blood pressure levels of patients with hypertension based on the published literature to date.A systematic search of all published randomized controlled trials (RCTs) on the effects of device-guided and nondevice-guided slow breathing in patients with hypertension, without language restriction, was carried out up to a publication date of January 2020 in nine databases: PubMed/MEDLINE, Latin American and Caribbean Health Sciences Literature (LILACS), EMBASE, CENTRAL , Physiotherapy Evidence Database (PEDro), CINAHL , Scopus, Web of Science, and Livivo. Clinical trial records databases , and bases for the open gray literature, including Gray Literature Report and ProQuest Central , were also searched for potentially eligible RCTs. The quality assessment of the included studies will be performed using the Cochrane Risk of Bias Tool for Randomized Trials. The overall quality of the evidence for each outcome will be assessed using the GRADE  system.As of December 2021, the review was completed and all data from continuous variables referring to blood pressure values (mmHg) were synthesized.This systematic review will provide a summary of the current evidence on the effects of both DGSB and NDGSB on blood pressure levels. This information can contribute to decision-making by health professionals related to the use of these interventions in patients with hypertension.PROSPERO  CRD42020147554; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=147554RR1-10.2196/33579 Hypertension is a multifactorial chronic disease, and is the main risk factor for the development of cardiovascular diseases and chronic kidney disease. Hypertension affects 32% of adults and more than 60% of the elderly, being responsible for half of the deaths from cardiovascular disease (CVD) in Brazil . In addiConsidering the high prevalence rates, the treatment of hypertension is necessary, not only to reduce blood pressure levels but also to prevent the development of CVD, cerebrovascular diseases, and kidney diseases. This treatment can be medication, which will be determined according to the blood pressure values obtained either in medical consultations or at home; cardiovascular risk factors; and the presence of target organ damage identified during anamnesis. Nonpharmacological treatment has also been shown to be effective in reducing blood pressure levels in patients with hypertension -4, incluThe physiotherapy prescription for the treatment of hypertension may include both exercise and device-guided slow breathing (DGSB) or nondevice-guided slow breathing (NDGSB). These breathing exercises consist of slow and deep breathing with 6 to 10 breaths per minute, and can be performed with or without a guiding device. Isometric exercises have been shown to be effective in reducing blood pressure levels, along with aerobic and dynamic exercises -6. HowevThe American Heart Association reported that there is no strong evidence on the effectiveness of DGSB, whereas the 8th Brazilian Hypertension Guidelines reported a IIa degree of recommendation, level of evidence A ,4. A revpranayama) for 4 weeks in patients with prehypertension and hypertension. The review included 17 studies, with systolic blood pressure reported in 1017 subjects and diastolic blood pressure reported in 964 subjects. Although interesting, this review did not specifically include patients with hypertension and exclusively compared DGSB to pranayama. Therefore, a systematic review of the antihypertensive effects of DGSB or NDGSB applied by physical therapists is necessary to provide the best evidence available to clinical physical therapists and patients with hypertension. In addition, it is also important to summarize the evidence on the effectiveness of DGSB or NDGSB compared to usual care.Recommendations for the use of DGSB or NDGSB in clinical practice should be guided by a systematic, high-quality literature review. Recently, Chaddha et al  publisheAccordingly, the aim of this systematic review and meta-analysis is to summarize the effects of DGSB on blood pressure levels of patients with hypertension compared with control conditions , other interventions (NDGSB), and when used as an adjunct to other treatments (medication). Thus, the research question for this systematic review of randomized controlled trials (RCTs) is: What are the effects of the prolonged use of device-guided or nondevice-guided slow breathing compared to usual care on the blood pressure values of patients with hypertension?The design of this systematic review is inspired by the recommendations of the Cochrane Handbook of Systematic Reviews  and the The articles were selected based on inclusion criteria according to the type of study, participants, and intervention.RCTs published up to January 2020 were included in this systematic review, without language or year of publication restrictions.Studies including patients with hypertension, with or without comorbidity, who were over 18 years old, of both sexes, and with or without antihypertensive medication treatment were included for review.Interventions considered had to involve DGSB and NDGSB compared to control conditions  and interventions as an adjunct to other treatments (medication). Any dosage of device-guided breathing treatment was accepted. Regarding the follow-up time, studies with a duration of a minimum of 8 weeks were considered.RCTs that also used other interventions along with DGSB/NDGSB, such as physical activity ; salt reduction and salt substitution; stress control ; dietary interventions, including a dietary approach to stop hypertension, low-carbohydrate diet, Mediterranean diet, high-protein diet, low-fat diet, vegetarian diet, paleolithic diet, and low index glycemic/load; and lifestyle interventions  were excluded since it was not possible to identify the specific effect of DGSB/NDGSB in such studies.The primary outcome was the systolic blood pressure and diastolic blood pressure values , expressed in mmHg, measured after the interventions, as well as their variations. The secondary outcome was a reduction in the quantity/dosage of drugs administered to control hypertension, if relevant.A systematic search of all published RCTs on the effects of device and nondevice-guided slow breathing in patients with hypertension, without language restriction, was carried out until January 2020 in nine databases: Pubmed/MEDLINE, Latin American and Caribbean Health Sciences Literature (LILACS), EMBASE, CENTRAL , Physiotherapy Evidence Database (PEDro), CINAHL , Scopus, Web of Science, and Livivo. Clinical trial record databases , and sites for the open grey literature, such as Gray Literature Report and ProQuest Central , were also searched. Completed and ongoing RCTs were searched up to January 2020 and, when possible, only peer-review papers were included, because the grey literature was also searched.An example of the search strategy used in PubMed/MEDLINE is shown in Two reviewers independently analyzed all titles and abstracts retrieved with the search. When there was agreement on a particular record, the full text was analyzed by both reviewers, according to the eligibility criteria. In the presence of disagreement between the reviewers, a third reviewer was convened. When additional information was needed, the authors of the potentially eligible studies were contacted.Hypertension [Mesh: NoExp], hypertensi*, high blood pressure, high blood pressures, blood pressure [Mesh], blood pressure, arterial pressures, arterial tension, arterial tensions, Arterial Pressure [Mesh], Arterial pressure, arterial blood pressure, arterial blood pressures, elevated blood pressure, acute hypertension, arterial hypertension, cardiovascular hypertension, controlled hypertension, hypertensive disease, systemic hypertension, increased blood pressure, artery blood pressure, artery pressure, systemic arterial pressure, systemic artery pressure, Hypertension [Mesh: NoExp] OR hypertensi* OR high blood pressure OR high blood pressures OR blood pressure [Mesh] OR blood pressure OR arterial pressures OR arterial tension OR arterial tensions OR Arterial Pressure [Mesh] OR Arterial pressure OR arterial blood pressure OR arterial blood pressures OR elevated blood pressure OR acute hypertension OR arterial hypertension OR cardiovascular hypertension OR controlled hypertension OR hypertensive disease OR systemic hypertension OR increased blood pressure OR artery blood pressure OR artery pressure OR systemic arterial pressure OR systemic artery pressure, Breathing Exercises [Mesh: NoExp], breathing exercises, respiratory muscle training, device-guided breathing, loaded breathing, slow breathing exercises, paced breathing, controlled breathing, breathing exercise, breathing therapy, chest physical therapy, chest physiotherapy, respiration exercise, respiration therapy, respiratory exercise, respiratory physiotherapy, deep inspiration, deep respiration, deep breathing, Breathing Exercises [Mesh: NoExp] OR breathing exercises OR respiratory muscle training OR device-guided breathing OR loaded breathing OR slow breathing exercises OR paced breathing OR controlled breathing OR breathing exercise OR breathing therapy OR chest physical therapy OR chest physiotherapy OR respiration exercise OR respiration therapy OR respiratory exercise OR respiratory physiotherapy OR deep inspiration OR deep respiration OR deep breathing OR deep respiration OR deep breathing, Hypertension [Mesh: NoExp] OR hypertensi* OR high blood pressure OR high blood pressures OR blood pressure [Mesh] OR blood pressure OR arterial pressures OR arterial tension OR arterial tensions OR Arterial Pressure [Mesh] OR Arterial pressure OR arterial blood pressure OR arterial blood pressures OR elevated blood pressure OR acute hypertension OR arterial hypertension OR cardiovascular hypertension OR controlled hypertension OR hypertensive disease OR systemic hypertension OR increased blood pressure OR artery blood pressure OR artery pressure OR systemic arterial pressure OR systemic artery pressure AND Breathing Exercises [Mesh: NoExp] OR breathing exercises OR respiratory muscle training OR device-guided breathing OR loaded breathing OR slow breathing exercises OR paced breathing OR controlled breathing OR breathing exercise OR breathing therapy OR chest physical therapy OR chest physiotherapy OR respiration exercise OR respiration therapy OR respiratory exercise OR respiratory physiotherapy OR deep inspiration OR deep respiration OR deep breathing OR deep respiration OR deep breathingTwo reviewers independently extracted the following data from the included trials: author, publication date, country of publication, study type, sample size, participant characteristics , use or not of antihypertensive medications, presence of comorbidities, categories of blood pressure, details of intervention , details for blood pressure measurement , and outcome measures (systolic and diastolic blood pressure). A third reviewer was called in case of disagreement. When necessary, the authors of RCTs included were contacted to provide additional information.The quality assessment of the included studies was conducted using the Cochrane Risk of Bias Tool for Randomized Trials (RoB2) , which iAll data from continuous variables referring to blood pressure values (mmHg) will be synthesized according to the mean difference and respective 95% CIs. Standard deviations were also extracted from the studies for analysis.The effects of interventions on blood pressure values will be analyzed separately. The data will be evaluated according to the type of intervention (DGSB or NDGSB); however, only studies lasting at least 8 weeks will be considered for meta-analysis . Results where there was an intention-to-treat analysis will be used whenever possible.2I statistic. The quality of the evidence will be considered inconsistent if considerable heterogeneity between the groups (2I>50%) is observed. When sufficient evidence is available, a funnel graph will be used to investigate possible publication bias.The presence of statistical heterogeneity between RCTs will be assessed using the 2I>50%), indirectness , imprecision (<400 participants in the comparison for continuous outcomes), and publication bias . For each factor not met, the quality of the evidence is reduced by one level . Single trial comparisons (<400 participants for continuous results) were found to be inconsistent and inaccurate, providing “low quality evidence,” which could be downgraded to “very low quality evidence” if limitations are identified in relation to the risk of bias [The overall quality of the evidence for each outcome will be assessed using the GRADE   system,  of bias .The quality of the evidence will be categorized as follows: the evidence is of high quality if the results are consistent in ≥75% of the participants, with a low risk of bias, without publication bias, and with consistent direct and accurate data; further research is unlikely to alter the estimate or confidence in such results. The evidence will be considered to be of moderate quality when one of the five classification factors above is met; further research can alter the estimated effect and impact confidence in the effect in this case. The evidence will be considered to be of poor quality when two of the five classification factors are not met. In this situation, future research is likely to alter the estimated effect and have a significant impact on confidence in the effect. The evidence will be considered to be of very low quality when three of the five classification factors are not met, as any estimate of effect is uncertain in this case .As of December 2021, the review is complete and all data from continuous variables referring to blood pressure values (in mmHg) have been synthesized.This systematic review aims to provide the best available evidence on the effectiveness of DGSB or NDGSB in patients with hypertension, as well as whether DGSB/NDGSB allows for a reduction in the amount/dosage of antihypertensive medication administration. All recommendations in the Cochrane Manual of Systematic Reviews will be followed to ensure that the review is of high quality. It is believed that the results of this systematic review will be important because both DGSB and NDGSB are accessible and can be performed even at home, as long as the use is prescribed and guided by a physical therapist.pranayama on the blood pressure of patients with hypertension, since this type of intervention is routinely used in a physiotherapist’s clinical practice, following a completely different method from that adopted in yoga. Therefore, this evidence will inform health care professionals and patients about the potential benefits of this intervention. This review may also identify gaps in the literature that can be addressed in future studies.In addition, this review is the first to assess NDGSB unrelated to the effect of


People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.The online version contains supplementary material available at 10.1186/s12882-021-02587-5. A significant percentage of people with diabetes develop chronic kidney disease (CKD), and diabetes is also a leading cause of end-stage kidney disease . Nearly Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor II blockers (ARB) are established treatment to slow the progression of DKD and reduce cardiovascular events. Novel agents such as sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid receptor antagonists and endothelin A receptor antagonists have recently been demonstrated to improve clinical outcomes and lower blood pressure, and are likely to be used in the routine management of DKD in the future .The scope of this update includes lifestyle advice, blood pressure targets and antihypertensive therapies in different categories of patients with DKD. Accurate measurement of blood pressure is vitally important before starting and during monitoring of antihypertensive treatment. Separate recommendation for blood pressure measurement has not been made in this guidance. We suggest the British and Irish Hypertension Society’s (BIHS) guidance on standardised, automated blood pressure measurement is followed. The blood pressure thresholds and targets in this guideline refer to standardised office blood pressure readings unless specified otherwise.This guidance is for a variety of clinicians who treat people with diabetic kidney disease, including primary care physicians and specialists in diabetes, cardiology and nephrology. It intends to harmonise practices of blood pressure monitoring, and pharmacological and non-pharmacological management of hypertension, which vary considerably in different settings.The guideline provides separate recommendations for type 1 and type 2 diabetes, with type 2 further divided into early (CKD stages 1–3) as well as advanced CKD (CKD stages 4–5), and dialysis patients  . SimilarThe threshold for diagnosis of hypertension in people with type 1 diabetes varies according to national and international guidelines. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest a blood pressure goal of ≤140/90 mmHg if urinary AER is under 30 mg per 24 h, or ≤ 130/80 mmHg if AER exceeds 30 mg per 24 h, although they do not distinguish between type 1 and type 2 diabetes . NationaThe role of home and ambulatory blood pressure measurement in the diagnosis and management of hypertension in people with type 1 diabetes and nephropathy is unclear. Small cohort studies of children and adults with type 1 diabetes suggest that an increase in nocturnal systolic blood pressure or blunting of nocturnal dipping is an important factor in progression to microalbuminuria in people with type 1 diabetes , 31. DueThe importance of lifestyle measures  are highlighted by a number of guidelines, and indeed a recent study suggests that lower sodium intake may improve the efficacy of RAAS blockade .There is evidence to suggest that management of blood pressure in people with type 1 diabetes may be suboptimal. In a large cross-sectional study of people with type 1 diabetes in Scandinavia, those on antihypertensive therapy who were achieving a blood pressure below 130/80 mmHg varied according to degree of albuminuria . Blood pAn important point to consider is the presence of postural hypotension in people with type 1 diabetes. Autonomic neuropathy is often associated with postural hypotension, and people with type 1 diabetes should have their supine and standing blood pressure checked. A significant drop in blood pressure on standing (> 20 mmHg) might alert the clinician to ensure that care is taken not to treat the person’s blood pressure over-aggressively. Otherwise we advocate the use of upright (sitting or standing) blood pressure as the target blood pressure, as per British Hypertension Society guidelines .There has been some interest in the use of agents that block the RAAS in the primary prevention of diabetic renal disease. The use of ACEIs has been tested in people who are normotensive and normoalbuminuric, and there is little evidence of a protective effect on the development of diabetic nephropathy. Importantly, however, many of these studies have used definitions of blood pressure that would now be considered to be too high. A multicentre European study examined 530 people with type 1 diabetes and blood pressure under 155/90 mmHg . The stuThe onset of microalbuminuria in someone with type 1 diabetes was once thought to lead to inevitable progression to macroalbuminuria and thence to progressive kidney disease . More reIn adolescents with type 1 diabetes, modest but persistent elevations of UACR in the normal range may be associated with progression to persistent microalbuminuria . FurtherIt is, however, recognised that the presence of microalbuminuria may not be the ideal risk marker for progressive renal dysfunction in people with type 1 diabetes . MicroalThere are few long-term studies that suggest that treating people with type 1 diabetes, microalbuminuria and normal blood pressure reduces end-stage kidney disease. There are, however, more short-term studies that focus on a change in AER rather than a change in renal function. A multicentre European study examined 79 individuals with microalbuminuria and blood pressure below 155/90 mmHg, and found a significant reduction in AER in the group of people who were treated with lisinopril compared with those who were treated with a placebo (− 34.2 mg/min) . In an 8RAAS blockade may have positive longer-term impacts on renal haemodynamics in people with type 1 diabetes even when therapy is stopped. In the 5-year Renin-Angiotensin System Study, people who were on RAAS blockade during the trial, but who stopped therapy after the trial, showed significantly greater renal haemodynamic responses to clamped hyperglycaemia and flow-mediated vasodilatation, which suggests that RAAS blockade has sustained, long-term protective effects .In people who are hypertensive and have microalbuminuria, however, there is relatively strong evidence to suggest that ACE inhibition slows progression of diabetic nephropathy in people with type 1 diabetes and microalbuminuria . Meta-an2) was 32%, and the cumulative incidence of end-stage kidney disease was 16% after 10 years, with better glucose and blood pressure control being the main factors associated with a lower risk of CKD progression. Therefore, while macroalbuminuria appears to be an important renal disease risk marker, it is far from inevitable that relentless progression to end-stage kidney disease will occur.For decades, the presence of macroalbuminuria in people with type 1 diabetes has been considered to be a stage of irreversible kidney disease. However, recent long-term follow-up of 159 individuals with type 1 diabetes in the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study showed that 10 years after onset of macroalbuminuria, the cumulative incidence of reduction to microalbuminuria was 52% . The cumSeminal studies in the 1980s suggested that early aggressive antihypertensive therapy could reduce the rate of decline of renal function in people with diabetic nephropathy , and furCandesartan has been studied in people with type 1 diabetes and diabetic retinopathy . A benefIt has been suggested that aldosterone escape during long-term RAAS blockade may be a mechanism by which ACE inhibition fails to prevent progressive renal disease in people with type 1 diabetes . Thus, tAliskiren, the direct renin inhibitor, has been trialled in people with type 2 diabetes and diabetic nephropathy, and no significant effect on renal outcomes has been noted, although a reduction in AER has been noted . A smallEarly studies of beta-blockade in people with diabetic nephropathy and type 1 diabetes suggest an equivalent effect to ACEI . There iThrough their ability to reduce intraglomerular pressure, blood pressure and uric acid levels, sodium glucose cotransporter-2 (SGLT-2) inhibitors may offer the possibility of renal protection. One study suggests that SGLT-2 inhibitors can offer a reduction in glomerular hyperfiltration . Recent Meta-analysis of a number of these studies of people with type 2 diabetes and nephropathy suggest a reduction in proteinuria, but at the expense of an increased risk of severe hyperkalaemia and episodes of acute kidney injury (AKI) –79. More2) in whom albuminuria is uncontrolled or increasing. While this may reduce albuminuria, there is no evidence of a reduction in other renal or cardiovascular end points.It is currently unclear whether there is a role for dual blockade in people who have type 1 diabetes and a normal eGFR . The presence of diabetic nephropathy increases cardiovascular morbidity and mortality and also increases progression to end-stage kidney disease –93. AfteThe risk of new as well as progressive microalbuminuria is significantly associated with high blood pressure . In peopDysregulation of the renin-angiotensin-aldosterone system (RAAS) plays a vital role in the pathogenesis of diabetic nephropathy, including pathogenesis of both micro- and macrovascular complications. Hyperglycaemia is associated with increased production of angiotensin II following RAAS over-activation in glomerular mesangial cells . Thus, mIn nearly one-third of people with type 2 diabetes, hypertension is present at the time of their diagnosis. Hypertension and type 2 diabetes may be related to underlying diabetic nephropathy, to co-existing essential hypertension or to renovascular disease, or it may be part of the complex insulin resistance syndrome. Hypertension in people with type 2 diabetes is generally associated with expanded plasma volume, increased peripheral vascular resistance and low renin activity .The threshold for diagnosis and aims for hypertension control in people with type 2 diabetes vary according to national and international guidelines. In the UK, for the management of hypertension in people with diabetes and for those with a UACR of 70 mg/mmol (619.47 mg/g) or more and CKD, NICE guidance recommends a target blood pressure of < 130/80 mmHg . The AmeThe KDIGO 2020 guidance suggests a stricter control in all individuals with CKD targeting a systolic blood pressure < 120 mmHg using a standardised blood pressure measurement technique, but acknowledges the lack of evidence in people who have diabetes and CKD .2.There is little evidence base for recommending blood pressure targets in older people who have CKD. Most randomised controlled trials excluded people who were over 70 years of age (mean age 65 years: about 2.5% were older than 85 years of age) but some indirect inferences can be drawn from studies of older populations who do not specifically have CKD. While there is some evidence regarding the treatment of high blood pressure in much older people  from the Hypertension in the Very Elderly Trial (HYVET) , it applThe Swedish Trial in Old Patients with Hypertension (STOP Hypertension), which compared antihypertensive treatments in preventing cardiovascular events in older people with diabetes (with a mean age of 75.8), supports an upright blood pressure target of no lower than 150/90 mmHg .The KDIGO guidelines  suggest Although home and ambulatory blood pressure monitoring is thought to be more representative of real-life blood pressure, their exact role in the diagnosis and management of hypertension is unclear because a limited number of studies have been conducted in people with type 2 diabetes who have CKD. However, it is recognised that high ambulatory blood pressure measurement systolic pressures and nocturnal non-dipping are associated with increased mortality and a decline in eGFR –108. A sThere is good evidence from a number of observational studies and randomised controlled trials that salt intake, weight and body mass index (BMI), exercise frequency and alcohol intake all have a significant impact on blood pressure levels –114. PleIn people with type 2 diabetes and CKD, three or more blood pressure agents are frequently required. There is increasing emphasis on individualisation of therapy. Eventually, the choice of agent is less important than the actual reduction in blood pressure that is achieved. There is little evidence to support the use of any particular agent in controlling blood pressure in CKD, nor are there any data to suggest the choice of second- or third-line medications. The exception to this rule is the use of ACEIs or ARBs in people with CKD who have proteinuria. ACEIs and ARBs have each been shown to be effective in delaying disease progression in people with type 2 diabetes who have microalbuminuria or established diabetic nephropathy. There is a need to escalate to the maximal doses of ACEI or ARB in people who have diabetes and albuminuria before moving on to additional agents in order to achieve the required blood pressure targets. However, there is no evidence that these agents are effective in the primary prevention of diabetic nephropathy. The use of ACEIs or ARBs in people with type 2 diabetes reduces microalbuminuria and retards the progressive loss of renal function , 126–128Non-adherence to antihypertensive treatment is common, with over 50% of people with apparent treatment resistance being non-adherent. This is especially so in those who are on multiple anti-hypertensive and other medications. Urine antihypertensive drug monitoring may help management of these individuals . Therefoany class of antihypertensive agent in people with diabetes in the absence of proteinuria, but suggest the use of RAAS blockade as first-line treatment only in the presence of proteinuria  . Howeverications . This truminuria . Howeveruminuria . Howeveruminuria .Several studies have shown that presence of significant albuminuria is associated with poor cardiovascular outcomes and reduction of albuminuria is associated improvement . Analysi2, use of the ACEI ramipril was associated with significant reduction in clinical composite outcome compared to metoprolol [22% ] or amlodipine [38% ] [p < 0.001] [2. Participants in large randomised controlled trials of people with diabetes had eGFR no lower than approximately 25 mL/min/1.73 m2 in REENAL and 38 mL/min/1.73 m2 in micro HOPE [In a study of African-American people without diabetes and with eGFR 20–65 mL/min/1.73 m 0.004)] . In a ra< 0.001] . In a re< 0.001] . Hence A< 0.001] , 210. A < 0.001] . Thus thcro HOPE , 212. Thcro HOPE , 214.2, there was no difference in mortality but a significant in increase in hyperkalaemia  and acute kidney injury  [In a study of combination therapy of ACEI with ARB in people who have diabetes with UACR  > 33.9 mg/mmol (300 mg/g) and eGFR 30–90 mL/min/1.73 m< 0.001] . Combina< 0.001] , 211.A rise in serum creatinine up to 30% is not uncommon and rise of potassium by 0.5 mmol/L is not uncommon with initiation of ACEI therapy . A post-Addition of spironolactone and further inhibition of the renin-angiotensin-aldosterone system may provide additional anti-proteinuric effect as seen in small studies and merits further large trials with more clinically relevant outcomes .Hyperkalaemia is common in people with diabetes and CKD. It is very common (> 30%) in advanced CKD patients managed in the low-kidney-clearance clinics . The cauTraditionally hyperkalaemia has been managed with dietary potassium restriction and correction of acidosis, if present with bicarbonate therapy. However, the new potassium binding agents have been tested for safety and efficacy in randomised controlled trials for management of chronic hyperkalaemia in CKD patients. They cause an early and sustained lowering of potassium in people with CKD on RAAS blocker therapy . In 306 > 6 mmol/L) and CKD stages 4 to 5 , who are not taking an optimised dosage of RAAS inhibitor because of hyperkalaemia [Novel potassium binders may be useful in diabetes patients with chronic kidney disease, particularly when associated with left ventricular dysfunction. Recent NICE technology appraisals recommend the use of potassium binders, patiromer and sodium zirconium cyclosilicate, in outpatient care for people with persistent hyperkalaemia  Renal Registry, 23–36% of incident dialysis patients had diabetes as their primary renal disease , 233. PeIt is therefore logical that, in order to reduce cardiovascular risk and improve survival, optimal blood pressure control should be achieved in people with diabetes and CKD stage 5D. However, there is insufficient evidence from data in the published literature to decide how best to manage blood pressure in people with diabetes who are on dialysis. This is in part because people with CKD, including those with stage 5D, are ‘often’ excluded from clinical trials of hypertension.There are emerging, although not consistent, data delineating how best to measure blood pressure, to target blood pressure and to use pharmacological and non-pharmacological therapies to optimise blood pressure control in people with CKD stage 5D. However, these data are not specific to the population with diabetes.Furthermore, blood pressure control in people who are on dialysis is complex. Many factors affect blood pressure in people who are on dialysis, including fluid status, salt intake, sympathetic nervous system activity and the renin-angiotensin-aldosterone system (RAAS). People with diabetes who are undergoing haemodialysis often have autonomic dysfunction , which iIn UK dialysis units, measuring pre- and post-dialysis blood pressure is the standard technique for monitoring blood pressure in people who are on dialysis. However, blood pressure measurement in people who are on haemodialysis is complex. There are conflicting data as to whether blood pressure measurements pre- and post-dialysis are predictive of interdialytic blood pressure in comparison with ambulatory blood pressure measurement and/or home blood pressure measurement. Ambulatory blood pressure measurement is considered to be the most accurate method for studying blood pressure in people who are on haemodialysis  and in tIn an extensive review of the literature by Agarwal et al , evidencWhile 24-h ambulatory blood pressure measurement (ABPM) is considered gold standard in predicting outcomes, it is resource intensive, impractical in for long-term monitoring of BP control and often not tolerated by individuals. Interdialytic home blood pressure (HBPM) is close to ABPM in predicting outcomes, but has high attrition rate for long-term monitoring. As routinely collected peri-dialytic BP measurements guide interventions in the majority of dialysis units, it is essential to ensure routinely collected dialysis unit BP readings are measured in a standardised manner in accordance with recommended guidelines.The relationship between blood pressure level and cardiovascular outcome is unclear in individuals who are on dialysis. Observational studies have shown an increased risk of mortality in people who are on haemodialysis who have a low pre- or post-dialysis systolic blood pressure of < 110 mmHg , and in Interestingly, in the Tassin group in France where the 5-year survival rate of 87% is the best reported in people who are on haemodialysis, the pre-dialysis blood pressure that was achieved was < 130/85 mmHg  < 101 mmHg) .Prospective randomised controlled studies on the effect of ARBs , ACEIs , beta blTwo meta-analyses have shown that blood pressure treatment in people who are on dialysis is associated with improved outcome. The first analysis was by Heerspink et al, published in 2009 . This meHowever, a randomised controlled trial by Agarwal et al in 2014 , includiIrrespective of the type of the antihypertensive agents that are used, the timing of the administration of such agents in relation to dialysis treatment needs to be taken into account when prescribing antihypertensive drugs for people who are on dialysis. ARBs, calcium channel blockers and alpha-blockers are not cleared with dialysis. However, ACEIs (apart from fosinopril) and a number of beta blockers are largely cleared on dialysis .To date, optimum blood pressure goals for individuals who are on dialysis (including people with diabetes) have not been defined in randomised prospective controlled trials . The KidFurthermore, people with diabetes who are on dialysis are at increased risk of haemodynamic instabilities and orthostatic intolerance post-dialysis, and therefore a blood pressure that is higher than 140 mmHg systolic may be indicated in the presence of significant orthostatic change in blood pressure. A randomised controlled trial is needed to identify the optimal blood pressure target for people with diabetes who are on dialysis.As for those who are on peritoneal dialysis, International Society of Peritoneal Dialysis (ISPD) guidelines recommend a target of < 140/90 mmHg for self-measured home blood pressure readings . HoweverIncreased extracellular volume or volume overload is an important contributor in the pathogenesis of high blood pressure in people who are on dialysis . RemovalIn the Tassin group, hypertension control without medication, achieved by aggressive control of extracellular volume and dietary sodium intake, was shown to be the best single marker of survival in 449 people who were on haemodialysis who were followed for 20 years .Observational studies showed that volume control is associated with improvement in blood pressure in the majority of people on haemodialysis  and periThe concept that ‘volume control’ improves blood pressure control is further supported by the increasing reports that daily dialysis , 280 or The risk of intradialytic hypotension increases with an ultrafiltration rate of > 10 ml/kg/hr. and was reported in the Dialysis Outcomes and Practice Patterns Study (DOPPS)  as an independent risk factor for mortality . This isBioimpedance spectroscopy devices , brain nReducing dietary salt to control blood pressure in people who are on dialysis was first reported by Hegstrom RM et al in 1961 . Salt reEvidence for the association between salt restriction and blood pressure control in people who are on dialysis comes from observational studies where dietary salt restriction was in combination with strict volume control. Craswell et al  (in a stIn a cross-sectional study by Kayikcioglu et al in 204 people on dialysis, dietary salt restriction to 5 g per day along with dialysate sodium reduction, led to a reduction in interdialytic weight gain, the number of antihypertensive medications and LVH . MaduellDiuretic therapy may provide an additional means by which to promote natriuresis in people who are on dialysis who have residual urine output. In the DOPPS study, Bragg-Gresham et al reported that diuretic use was associated with reduced interdialytic weight gain, fewer intradialytic hypotensive episodes and reduced cardiac-specific mortality, but not all-cause mortality . People Interestingly, and independent of its diuretic property, spironolactone has been shown, in a randomised controlled trial that included participants with diabetes, to be more effective than placebo in treating refractory hypertension in people on dialysis . There iTo date there have been no randomised controlled trials to address the question of whether salt restriction or diuretic use in people with diabetes who are on dialysis may influence blood pressure control or cardiovascular outcome. In the absence of such evidence, individualisation of dietary sodium intake is required, depending on the person’s interdialytic weight gain, extracellular volume status, haemodynamic stability and nutritional status.There are areas which require further investigation including randomized controlled trials to further improve care of people with diabetes and CKD as highlighted in Table People with diabetes and CKD have increased risk of morbidity and mortality. They experience excess cardiovascular events and progression of CKD. Hypertension is a common risk factor for both adverse outcomes. Tight control of blood pressure and the use RAAS inhibitors are associated with improved outcomes, particularly in the presence of proteinuria. RAAS inhibitors can cause side effects e.g. rising serum creatinine and hyperkalaemia. However, guideline-based therapy such as mentioned here can prolong life, lower risk of cardiovascular events and hospital admissions, and prevent end-stage kidney failure requiring renal replacement therapy.Additional file 1.


Purpose: It is well known that anticancer drugs used for treating breast cancer can cause cardiac toxicity, and less is known about vascular toxicity. The aim of this study was to assess subclinical vascular effects of anthracyclines and trastuzumab (TRZ) in women treated for breast cancer.Methods: We enrolled 133 female patients with breast cancer undergoing adjuvant treatment with anthracycline-containing chemotherapy (CT) followed by taxane (paclitaxel/docetaxel) + TRZ. Patients underwent a standard echocardiography including measurement of left ventricular ejection fraction and global longitudinal strain at baseline and at follow-up. Vascular toxicity was evaluated by measuring brachial blood pressure (BP) and arterial stiffness indices (pulse wave velocity and Beta stiffness index) at T0 (baseline), T1 (3 months), T2 (6 months), and T3 (12 months).Results: Arterial stiffness indices were significantly increased at T1 in patients treated with anthracycline-containing CT  but not at T2 and T3, when treatment with anthracyclines was stopped and patients were under treatment with taxane and TRZ. Blood pressure values did not significantly change during follow-up.Conclusion: Changes in arterial stiffness parameters occur early after starting treatment with anthracyclines, and they seem to be reversible if anthracycline treatment is stopped. These changes are not influenced by blood pressure values modifications. Therefore, in breast cancer women, anthracyclines seem to cause early reversible subclinical vascular injury. Cardiotoxic effects of anthracyclines and their mechanism have been extensively studied . It is kAfter their informed consent was collected, 133 consecutive female patients with diagnosis of breast cancer were enrolled. The study was approved by the Ethics Committee of the University Hospital P. Giaccone in Palermo. Inclusion criteria were new diagnosis of breast cancer, basal left ventricular ejection fraction (LVEF) >50%, absence of coronary artery disease and hemodynamically significant valvular heart disease, absence of carotid atherosclerotic plaques, absence of significant comorbidities, and adequate echocardiographic imaging before starting anthracycline-containing CT in adjuvant setting. Exclusion criteria were age under 18, preexisting left ventricular dysfunction before starting chemotherapy, and severe liver and renal dysfunction. Careful clinical history was collected, and the presence of cardiovascular risk factors was evaluated . All patients underwent blood pressure measurement, electrocardiogram with QTc interval measurement, standard transthoracic echocardiogram, and carotid ultrasound scan with arterial stiffness measurement at baseline before starting CT (T0), at 3 (T1), 6 (T2), and 12 (T3) months. The CT protocol included anthracycline for four cycles with an inter-cycle interval of 21 days (3 months-T1). After anthracycline-based CT, patients continued treatment with taxane , trastuzumab , radiotherapy (51%), and endocrine therapy (37%).Standard echocardiogram was performed using a Vivid E9 ultrasound machine  equipped with a 2.5 MHz transducer and included speckle tracking analysis . Chamber and ventricular function quantifications were measured according to the ASE/EACVI guidelines . Diastolβ. PWV is the travel speed of the pulsed wave and is expressed in meters per second. The parameter β indicates the degree of atherosclerosis, and it increases in the presence of atherosclerosis.Carotid arteries ultrasound scan was performed using an Esaote machine (MyLab Twice) with a high-resolution 12 MHz linear sequence transducer. The device was equipped with RF Quality Intima-Media Thickness Analysis and Radiofrequency (RF) Quality Arterial Stiffness (QAS) analysis software. This software measures arterial stiffness at a single region of interest , by monitoring arterial wall movements, by RF signals, in systolic and diastolic phases during six cardiac cycles, in B mode examinations, and it is able to detect micrometric variations of the artery diameter. The arterial distension waveform is combined with the brachial artery blood pressure (BP), which was measured after approximately 10 min of resting, before starting the examination and recorded in the device. Among the detectable parameters, we reported PWV and parameter Age- and sex-specific percentiles of local carotid stiffness in healthy population were reported in the literature.p < 0.05. All analyses were performed using the MedCalc Statistical Software version 19.2.1 .Quantitative variables are reported as mean and standard deviation (SD) or median and interquartile range (IQR) according to data distribution analysis as verified by D’Agostino–Pearson test; qualitative variables were reported as percentage. ANOVA was performed using Friedman test. Multiple regression analysis has been used to evaluate the influence between variables. Differences were considered significantly if p < 0.05), but there were no any significant variations at T2 (6.72 IQR 5.5–8.1) and T3 (6.9 IQR 5.75–9) compared to baseline. We also found a statistically significant increase in PWV at T1 ; accordingly, variation was not significant at T2 (5.75 m/s IQR 5.2–6.7) and T3 , while pressures lost predictivity at T1 (p > 0.05).p < 0.05); at T2 (59% IQR 55–61) and T3 (58% IQR 56–60), we observed a significant reduction in LVEF compared to baseline (p < 0.05). A significant reduction in GLS was observed at T1 , T2  and T3  compared to baseline . Thus, GLS significantly reduced at T1 and persistently reduced at T2 and T3.Regarding the echocardiographic evaluation, no statistically significant changes in LVEF were observed at T1 (60% IQR 58.2–64.2) compared to baseline  and it seems to be reversible.Subclinical cardiac dysfunction occurs early and persists over time. In addition, as already known, the reduction in GLS precedes the reduction in LVEF during chemotherapy.β parameter) at T1; then, it improved at T2 and T3. Our data are in agreement with the few studies present in the literature to date  and vascular (acute and early reversible) anthracyclines toxicity, respectively.Pulse wave analysis is a reliable, noninvasive, cheap, and practical technique. A limitation of our study is the lack of validated standard measurement of arterial stiffness such as carotid–femoral PWV. This is a limitation but also the novelty of our study because single-point measurement of arterial stiffness by QAS has not been used in previous studies. This technique is much more feasible in the clinical context and less time consuming compared to tonometer. It can be performed with the same machine used for echocardiographic examination, and it is only needed to switch the cardiac probe with the linear one and to set the specific software.Several studies have demonstrated that arterial stiffness is predictive of vascular events ; howeverThus, in conclusion, our study confirms that stiffness indexes change early during treatment with anthracycline and this is not a consequence of modifications in blood pressure values. Vascular damage in course of anthracyclines treatment is an acute and reversible damage.giuseppina.novo@unipa.it).The datasets presented in this article are not readily available. Requests to access the datasets should be directed to Giuseppina Novo (The studies involving human participants were reviewed and approved by A.O.U. Policlinico Paolo Giaccone. Informed consent was obtained from all individual participants included in the study.All authors contributed to the writing. GM submitted the manuscript. GN, DL, AR, LI, and CZ are the coordinators of the study. FI and CM analyzed the statistics. LI and CZ are co-last authors. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To assess the trends in cardiovascular risk factor control and drug therapy from 2007 to 2018 in subjects with type 2 diabetes mellitus (T2DM).Cross-sectional analysis using yearly clinical data and treatment obtained from the SIDIAP database. Patients aged ≥18 years with a diagnosis of T2DM seen in primary care in Catalonia, Spain. The number of T2DM patients increased from 299,855 in 2007 to 394,266 in 2018. We also found an increasing prevalence of cardiovascular disease, heart failure, and chronic kidney disease . The achievement of glycemic targets (HbA1c<7%) scarcely changed (54.9% to 55.9%). Major improvements were seen in blood pressure (≤140/90 mmHg: from 55% to 71.8%), and in lipid control (low-density lipoprotein cholesterol <100 mg/dl: 33.4% to 48.4%), especially in people with established cardiovascular disease (48.8 to 69.7%). Simultaneous achievement of all three targets improved from 12.5% to 20.1% in the overall population and from 24.5% to 32.2% in those with cardiovascular disease but plateaued after 2013. There was an increase in the percentage of patients treated with any antidiabetic drug (70.1% to 81.0%), especially metformin (47.7% to 67.7%), and DPP4i (0 to 22.6%). The use of SGLT-2 and GLP-1ra increased over the years, but remained very low in 2018 . There were also relevant increases in the use of statins (38.0% to 49.2%), renin-angiotensin system (RAS) drugs (52.5% to 57.2%), and beta-blockers (14.3% to 22.7%).During the 2007-2018 period, relevant improvements in blood pressure and lipid control occurred, especially in people with cardiovascular disease. Despite the increase in the use of antidiabetic and cardiovascular drugs, the proportion of patients in which the three objectives were simultaneously achieved is still insufficient and plateaued after 2013. The use of antidiabetic drugs with demonstrated cardio renal benefits (SGLT-2 and GLP-1ra) increased over the years, but their use remained quite low. Type 2 diabetes mellitus (T2DM) is a global health problem due to its high worldwide prevalence, high cost of management, associated chronic complications, disability, and premature deaths . Tight gSeveral studies have been published showing changes in the prescription of antidiabetic drugs –18. In tThe healthcare system in Catalonia (Spain) is public and universal, where the primary care centers provide first contact and continuing care for persons with any health concerns, and they are usually the principal place where T2DM is diagnosed and managed. The antidiabetic treatment is free of charge for retired and severely ill people, while active subjects pay just a small part of the cost of the drugs. Since 2006, a system of electronic medical records (EMR), called e-CAP, was fully implemented in primary care, which allowed the creation of the SIDIAP population database , 20. To Due to important changes in the therapeutic guidelines, we hypothesized that there would be changes in the control of cardiovascular risk factors (CVRFs) and pattern of use of antidiabetic drugs in our T2DM population. Our study aimed to describe the degree of control and treatment pattern related to CVRFs during 2007-2018 in primary care centers in Catalonia (Spain).We obtained annual cross-sectional data from 2007 to 2018 using the primary health care SIDIAP database. This database includes secondary pseudo-anonymized routinely collected health data from subjects attended in the primary health care centers (PHCCs) of the leading health care provider in Catalonia (Spain), the Catalan Institute of Health . The SIDIAP database is a well-recognized and valid database for the study of diabetes, including EMR, clinical and laboratory parameters, and medicine prescription and dispensation data. In 2018, the ICS managed 288 PHCCs that served 5,672,956 registered citizens, 75.2% of the Catalan population.We included all subjects 18 years or older with a diagnosis of T2DM in the database defined by the International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnostic codes (E11 or E14 and sub-codes). We excluded all subjects with diagnostic codes of other types of diabetes such as type 1, gestational, or other .For each year evaluated, the “cut-off” date was defined as December 31st. We collected variables related to the social-demographic characteristics  and duration of T2DM. Comorbidities, such as hypertension and hypercholesterolemia, were defined on the base of the specific diagnostic code and/or drug treatment for any of these conditions. Peripheral artery disease, cerebrovascular disease, heart failure, ischemic heart disease, peripheral neuropathy, retinopathy as well as composite variables for microvascular and macrovascular complications were defined by the diagnostic codes of these conditions. Chronic kidney disease (CKD) was defined by the specific diagnostic code and/or the combination of CKD-EPI glomerular filtration rate <60 ml/min/1,73m2 and/or an albumin/creatinine ratio >30mg/g. The closest measurement to the “cut-off” date for clinical variables (systolic and diastolic blood pressure and body mass index -BMI) and laboratory parameters  were considered. Drug treatment dispensations during the whole year  were collected. Six steps of antidiabetic treatment were considered: non-pharmacological therapy (no drugs), non-insulin antidiabetic drug (NIAD) monotherapy, NIAD double therapy, NIAD triple therapy, insulin alone and insulin in combination. The non-pharmacological therapy was defined if there were no records for dispensing antidiabetic drugs during the previous year. Monotherapy was defined for NIADs and insulin separately. Dual therapy was defined as a combination of two NIADs, while triple therapy was a combination of three NIADs. Insulin in combination included all subjects with insulin in combination with any NIAD.Descriptive analysis for study variables was done for each year of observation. We calculated mean and standard deviation for all quantitative variables, and frequencies and percentages for qualitative variables. We calculated the degree of glycemic, blood pressure, and lipid control and the use of antihypertensive, lipid-lowering, antithrombotic, and glucose-lowering therapies. According to local and international guidelines, glycemic control was defined at an HbA1c level below 7%; we also used an HbA1c threshold below 8%, which is the pay-for-performance goal at our institution (ICS). We used the mean of all available BP measurements  to estimate each patient’s systolic and diastolic BP. BP control was defined as a systolic/diastolic BP level equal or less than 140/90 mm Hg. Cholesterol control was defined as having an LDL-C level less than 100 mg/dL. We further defined a composite indicator using the three outcomes . LDL-C control and the combined indicator were analyzed globally and separately in people with and without cardiovascular disease (CVD). Additionally, we performed trend tests to analyze whether the reported changes were statistically significant. For the continuous variables, we applied one-factor ANOVA, where the factors were the different year periods we wanted to compare (2007-2018). For categorical variables, we used the “prop_trend_test” function of the R Package rstatix (version 0.7.0). This function performs chi-squared test to assess the trend in proportions. Data management and all analyses were performed using R statistical software, version 3.6.3. (2020/02/29).The studies involving human participants were reviewed and approved by Institutional Review Board (or Ethics Committee) of IDIAP Jordi Gol i Gurina Foundation . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Characteristics of the study subjects at each time-point of the study are presented in Concerning comorbidities, hypertension and dyslipidemia were highly prevalent among T2DM subjects; both increased over the years. The prevalence of chronic diabetic complications also increased progressively. We observed a progressive decrease in BP and LDL-C mean values while BMI and HbA1c did not show any relevant changes.Trends in HbA1c levels are presented in Trends in achieving the therapeutic goals are presented in Major improvements were seen in the proportion of people with blood pressure control (≤140/90 mm Hg), from 55% to 71.8%  was observed in the registered T2DM population, and in the prevalence of cardiovascular disease, heart failure, and chronic kidney disease . This could be probably due to an improvement in registration and the aging population. In fact, there was an increase in the mean age (from 68.4 to 70.3 years) and in the percentage of patients older than 75 (from 32.7% to 37.6%). The unexpected low diabetes duration could be explained by the EMR system (eCAP), which was widely introduced in 2006 in Catalonia. The accuracy of patients’ diagnosis dates reported in the first years could be affected by memory, while further diagnoses based on laboratory results were probably more accurately registered after the implementation of the eCAP. There was also an increase in the records of chronic complications, especially chronic kidney disease (CKD), retinopathy, and heart failure. At the end of the study, nearly a quarter of patients (24.4%) had CVD and 31% CKD. These figures align with those of other studies on the prevalence of chronic complications , 22.Concerning the control of CVRFs, greater improvements have been observed for cholesterol and BP than for glycemic control, as described in previous reports in the US and the UK –12. In oMajor improvements were seen in the percentage of people achieving target blood pressure, from 55% to 71.8%. The same trend was seen for LDL-C targets: 33.4% to 48.4%, especially in people with CVD: 48.8% to 69.7%. Nevertheless, only one in five patients achieved all three risk factor control goals, increasing from 12.5% to 20.1% in the whole population, but stagnation occurred after 2013. This improvement was greater for those with CVD (from 18.7% to 28.3%), probably due to more intense treatment with lipid-lowering drugs. Published data from the US, based on NHANES surveys from 1999 to 2018, showed a worsening of glycemic control (HbA1c<7%) between the 2007–2010 and 2015–2018 surveys: from 57.4% to 50.5% of people achieving this target  study as mentioned earlier: 56.3% used statins, and 60.3% used a RAS antihypertensive . Use of This study has some strengths and limitations. The main strength is that we used a large database to determine trends in primary care. However, this was a retrospective study, and missing data should be noted, especially in the first years of the study. For instance, the percentage of missing values for HbA1c was 36.9% in 2007, which decreased to 25% in 2018. This was also the case for the available values for calculating the combined 3 CVRF indicators: only 48.9% of patients had both three measurements in 2007 but this increased to 62.1% in 2018. Lack of data could be explained due to some patients not attending their routine visits, incomplete recording of patient information by some health professionals, and that a small proportion of subjects are under the care of endocrinologists in hospitals or private clinics. In studies like the current one that include a very large sample of participants, even small differences are statistically significant. Actually, the statistical differences found in our study do not add relevant information for the final interpretation of the findings. Nevertheless, a large number of measurements and the consistency of similar annual results contribute to the validity of our conclusions.In conclusion, in our country, during 2007-2018, relevant improvements were observed in blood pressure and lipid control, especially in people with cardiovascular disease. Despite the increase in the use of antidiabetic and cardiovascular drugs, the proportion of patients in which the three objectives were simultaneously achieved is still insufficient and plateaued after 2013. Finally, the use of antidiabetic drugs with demonstrated cardio renal benefits like SGLT-2 and GLP-1ra increased over the years, but their use remained very low.josep.franch@gmail.com.The data analyzed in this study is subject to the following licenses/restrictions: The data controller for SIDIAP does not allow the sharing of raw data. Requests to access these datasets should be directed to JF-N, The studies involving human participants were reviewed and approved by Institutional Review Board (or Ethics Committee) of IDIAP Jordi Gol i Gurina Foundation . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.MM-C and BV have contributed equally to this work and share the first authorship. MM-C, JF-N, JR, RP-T, MB, DM, and BV conceived the research and participated in its design. JR and RP-T performed statistical analysis. MM-C and BV wrote the initial draft of the manuscript, which MM-C, JF-N, JR, RP-T, MB, DM, and BV edited. All authors contributed to the article and approved the submitted version.MM-C has received advisory honorarium from Astra-Zeneca, Bayer, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; he has received speaker honorarium from Astra-Zeneca, Bayer, Boehringer Ingelheim, GSK, Lilly, Menarini, MSD, Novartis, Novo Nordisk, and Sanofi; he has received research grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, Novo Nordisk and Sanofi. JF-N has received advisory and or speaking fees from Astra-Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; he has received research grants to the institution from Astra-Zeneca. GSK, Lilly, MSD, Novartis, Novo Nordisk, Sanofi, and Boehringer. DM has received advisory and/or speaking fees from Astra-Zeneca, Ascensia, Boehringer Ingelheim, GSK, Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; he has received research grants to the institution from Astra-Zeneca, GSK, Lilly, MSD, Novartis, Novo Nordisk, Sanofi, and Boehringer. MB has received advisory and speaking fees from MSD.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.