Uncontrolled arterial hypertension is a major global health issue. Catheter-based renal denervation has shown to lower blood pressure in sham-controlled trials and represents a device-based, complementary treatment option for hypertension. In this situation assessment, the authors, who are practicing experts in hypertension, nephrology, general practice and cardiology in the Republic of Ireland, discuss the current evidence base for the BP-lowering efficacy and safety of catheter-based renal denervation with different modalities. Although important questions remain regarding the identification of responders, and long-term efficacy and safety of the intervention, renal denervation has the potential to provide much-needed help to address hypertension and its adverse consequences. The therapeutic approach needs to be multidisciplinary and personalised to take into account the perspective of patients and healthcare professionals in a shared decision-making process. Uncontrolled arterial hypertension is a global health issue of enormous dimensions. Pooled data analysis from 2019, shows a global age-standardised prevalence of hypertension in adults 30–79 y) of 32%  30–34) in women and 34% (95% CrI 32–37) in men  presented at the ACC in November 2022 showed no significant difference in 24 h ambulatory BP in the RDN-arm in comparison to the sham control-arm. But the absolute reduction in BP by RDN was consistent with the previously published data on RF-based RDN and office BP was still significantly lower in the RDN-arm. The fact that patients in the sham-control arm had a significantly higher medication burden and part of the 24 h ABPM was assessed during the COVID-19 pandemic relativises the unmet primary endpoint . These difficulties show the challenges associated with clinical trials of an interventional therapy in hypertensive patients.Within the limits of current clinical experience with the technique, available data indicate that RDN has a very favourable safety profile. By design of the interventional therapy, mainly three safety aspects are to be discussed. n = 506) reported a single pseudoaneurysm that had to be treated with IV thrombin injections [First, the risk of vascular access complications. In the randomised controlled SPYRAL trials, no vascular access site complications were reported ,22,23. Pjections .2, reduction by 7.1  ±  16.7 mL/min/1.73 m2)  than with renal dysfunction  mL/min/1.73 m2), both values lie within the range of the expected decline in renal function of patients with arterial hypertension [2 was an exclusion criterion in all of the sham-controlled RCTs and the assessed safety profile cannot be generalised to patients with a higher degree of kidney dysfunction. In the ongoing SPYRAL AFFIRM global study (NTC05198674), an eGFR of <30 mL/min/1.73 m2 was chosen as an exclusion cut-off, thus allowing the collection of efficacy and safety endpoints in patients with a higher degree of renal dysfunction.Second, contrast-induced kidney injury. None of the above mentioned RCTs reported a significant change in creatinine from baseline to follow-up or major contrast-induced kidney injury ,22,23,31rtension . A meta-rtension . Of noteThird, injuries at the kidney level such as renal artery stenosis, parenchymal lesions, embolic events and organ tissue damage. Acute risks include micro injuries to the renal arteries, which have been documented using intravenous ultrasound and optical coherence tomography . No clinAlthough procedures were done with a first generation device (SYMPLICITY Flex ™), long-term results from the SYMPLICITY HTN-3 Trial did not show a significant difference in the composite safety endpoint  at 36 months across the three groups  .n = 102), with 89.7% of participants achieving an office SBP reduction of ≥10 mmHg [Post hoc analysis of the SYMPLICITY HTN-3 trial showed a non-significant treatment response in the African American subpopulation. Although the potential influence of ethnicity cannot be ruled out, as discussed above, a major confounder seems to be the changes of medication in this subgroup (39% from baseline) . To date≥10 mmHg . SYMPLIC≥10 mmHg . Furthern = 535) consisting of the original treatment group, and the original sham group with and without cross-over were analysed [p ≤ 0.0001). Also, 24 h-SBP was significantly lower in the RDN group at 36 months, −15.6 mmHg (±20.8) vs. −0.3 (±15.1) for the sham group (adjusted treatment difference −16.5 mm Hg (95% CI −20.5 to −12.5); p ≤ 0.0001). The treatment effect seemed to be progressive over time [n = 80) showed a persisting significant treatment difference between both groups in favour of the RDN group at 36 months [p = 0.0039) [p = 0.021 [The sustainability of the antihypertensive effect of RDN is a relevant question with only limited data available at present. The best data available for long-term outcomes after RDN comes from the SYMPLICITY HTN-3 trial . At 36 manalysed . At 36 mver time . Yet agaver time . A non-cver time . Long-te6 months . Showing 0.0039) . In thei 0.0039) . In comp = 0.021 .Medication burden may be a surrogate for long-term efficacy of RDN. In RADIANCE-HTN SOLO, the number of drugs needed to control BP at 12 months was significantly lower after RDN than after sham-procedure . In the p < 0.001), while office SBP was reduced by 7 ± 23 mmHg (p < 0.02) [Limited data are available from follow-up of more than 3 years. A recent prospective single arm interventional study reported 48 months follow-up data of 49 patients treated for resistant hypertension . Patient < 0.02) .Hypertension is a well-accepted surrogate marker of CV risk and long-term reductions in BP can be expected to reduce the risk of clinical outcomes . Large sp < 0.01 [p < 0.01) [A probabilistic analysis based on the mean cohort changes in office SBP in the Global SYMPLICITY Registry indicated a significant reduction in MACE  over 3 years after RDN MACE rate 8.6% (±0.7%) vs. 11.7% (±0.9%) in a projected control group without treatment, p < 0.01 . This re < 0.01) . While nThe potential of long-term reduction of adverse CV events by reducing BP raises the question of cost-effectiveness of RDN as a one-in-a-lifetime procedure . Early tThe available data indicate that RDN has proven BP-lowering effects and a good safety profile. Although the handful of RCTs demonstrated antihypertensive effects in a heterogeneous patient population, the challenge to identify responders and non-responders to RDN remains. Real-life data from the Global SYMPLICITY Registry indicate a similar effect on BP levels from RDN among patients with varying CV risk and comorbidities ,72.The ‘always on’ effect of the intervention appears to produce more consistent BP reduction than pharmacotherapy even when the latter is taken regularly. Hence, it may be a particularly beneficial option in subjects with higher-than-expected nocturnal BP (non-dippers and reverse dippers) or those with a large early morning surge in BP, particularly in older people. Both conditions are associated with increased CV risk ,75,76,77The ‘always on’ effect and once in a lifetime procedure is an advantageous feature of RDN for BP control, especially in the context of non-adherence to pharmacotherapy due to polypharmacy ,78,79. AAs mentioned above, RDN has proven its efficacy and safety in patients with and without antihypertensive medication in resistant and/or uncontrolled arterial hypertension. Considering the achieved treatment effect by RDN, this interventional treatment seems to be a complementary tool to control BP alongside the state-of-the-art pharmacotherapy.Cardiology: Dr. M. Wagener, Dr. S. Arnous, Prof. J. Galvin, Prof. I. Casserly, Dr. S. O’Connor, Dr. C. McCreery, Dr. J. Shand, Dr. S. Mattiullah, Prof. F. Sharif; Stroke and Hypertension: Dr. E. Dolan; General Practice: Prof. A. W. Murphy; Nephrology: Prof. J. Eustace, Prof. C. Wall.The following consensus points have been elaborated based on clinical expertise and an extensive literature review by a multidisciplinary national advisory board. Specialists of the following disciplines are represented in this advisory board: Insufficiently controlled BP is a large public health problem and greater control of BP is needed to reduce adverse outcomes.This point has been made for decades, and remains even more relevant today.A multidisciplinary team should be involved in the diagnosis and treatment of resistant and uncontrolled hypertension.As has been noted by other experts, most patients with hypertension encountered in routine clinical care will not have difficult-to-treat, let alone resistant, hypertension. A multidisciplinary evaluation is necessary to exclude secondary causes, and identify possible hypertension-mediated organ damage or severe comorbidities, which would increase the need and urgency to reduce BP. We encourage the setting up of multidisciplinary refractory hypertension clinics with input from cardiology, endocrinology, nephrology and clinical pharmacists.Patient involvement in shared decision-making should be encouraged.Paternalistic medicine has long had its day. Guidelines and expert opinion statements on hypertension treatments have long acknowledged the individual responsibility for BP management and the overall importance of patient involvement. Treatment decisions should be taken together between physicians and patients and include the generation of personal risk profiles, as well as an informed discussion of patient preferences, motivation and treatment expectations, including patient tolerance for risk and perspective on benefit . One proRenal denervation is effective at lowering BP and appears safe.The guiding rule when deciding on the appropriateness of an intervention is that the procedural risk must not exceed the underlying risk of the untreated condition for each individual patient. As was discussed in detail above, this is considered well demonstrated for RDN in hypertension. Renal denervation should prioritise patients with uncontrolled hypertension and elevated CV risk and those with established organ damage.RDN was initially trialled in patients with resistant hypertension, but there are several reasons why this may not be the most appropriate target group. The term ‘resistant hypertension’ is overused and different guidelines define it in different ways. US guidelines recommend to limit its application to subjects with office SBP/DBP ≥ 130/80 mm Hg, despite prescription of ≥ three antihypertensive medications at optimal doses, including a diuretic if possible or a requirement of ≥ four antihypertensive medications to achieve an office SBP/DBP < 130/80 mmHg (diastolic BP = DBP) . ESC guiEuropean and US consensus statements on RDN prioritise patients with uncontrolled hypertension and elevated CV risk, possibly with established CV event or organ damage ,13,16. WCentres performing renal denervation should asses efficacy and safety endpoints, as well as follow-up data in patients undergoing renal denervation in standardised and auditable databases.Office BP measurements as well as ABPM should be considered as standard of care to assess the efficacy of treatment post RDN. The optimal timepoint for follow-up is yet to be defined in the context of a progressive treatment effect over time as published in the trials. The collection of data is imperative to grant high procedural standards and optimise patient selection and outcomes. It allows auditing the efficacy and safety of a novel treatment and identifying any potential futility of efficacy in real-world patients.The long-term effects of RDN will become evident as registries continue to follow up treated patients. In the context of the non-responder (a < 5 mmHg reduction in SBP after RDN) rates in the absence of antihypertensive drugs, 37% in SPYRAL HTN-OFF MED and 36% in RADIANCE HTN-Solo, there is an unmet need to identify predictors of response ,11. All Variability in baseline BP levels and changes in medication or adherence during follow-up make it very difficult to identify true responders in a study population ,48. PostAt the time of writing, only the level of BP at baseline has been confirmed to be a reliable indicator of response. However, this goes for most antihypertensive treatments and may be in part due to Wilder’s law of initial value, which states that the direction of response of body function to any agent depends to a large degree on the initial value of that function . In the Procedural success has been reported to drive the response to RDN: in SYMPLICITY HTN-3, insufficient denervation was one of the factors driving the neutral outcome . Post hoAlthough CV outcome-driven clinical trials for RDN are pending, the effect size achieved with RDN and the proven MACE reductions after medication-induced BP reductions, as well as the probabilistic models of MACE reductions in the Global SYMPLICITY Registry give no reasons to doubt the potential for MACE reductions after RDN-based BP control ,67,68.It is our opinion that RDN should be considered an important emerging tool in the management of hypertension. The therapeutic approach needs to be multidisciplinary and personalised to take into account the perspective of patients and healthcare professionals in a shared decision-making process. Important questions regarding the identification of responders, as well as long-term efficacy and safety of the intervention are to be met. But today’s clinical results and experience with the intervention should reassure physicians and patients that RDN can provide much-needed help to address hypertension and its adverse consequences. For now, the use of RDN in Ireland should be limited within research registries and centres of excellence. Though in the future, as more evidence for efficacy and cost-effectiveness emerges to inform changes to hypertension clinical practice guidelines, it is hoped that RDN will become an option for all patients and healthcare providers to consider.


Current guidelines recommend office blood pressures (BP) be taken in a seated position when screening for hypertension (HTN). Seated BP is known to have limited accuracy in detecting high BP, while the utility of standing BP in diagnosing HTN is unknown. We conducted a cross-sectional study to determine the incremental value of standing BP in diagnosing HTN. Seated, standing, and 24-h ambulatory BPs (ABPM) were obtained in adults without known cardiovascular disease, HTN, or BP medication use. Presence of HTN was defined by the 2017 ACC/AHA and the 2023 ESH HTN guidelines based on ABPM. Area under the receiver-operating-characteristic curve (AUROC) was used to evaluate the diagnostic accuracy of seated and standing BP. Sensitivity and specificity of standing BP was determined using cut-offs derived from Youden’s Index, while sensitivity and specificity of seated BP was determined using the cut-off of 130/80 mmHg and by 140/90 mmHg. Among 125 participants , 33.6% of them had HTN. Sensitivity and specificity of seated systolic BP (SBP) was 43% and 92%, respectively. Cut-offs selected by Youden’s index for standing SBP/diastolic BP (DBP) were 124/81 mmHg according to the 2017 ACC/AHA HTN guidelines, and 123.5/83.5 mmHg according to the 2023 ESH HTN guidelines. Sensitivity and specificity of standing SBP was 71% and 67%, respectively. The AUROC of standing SBP (0.81 [0.71–0.92]) was significantly higher than seated SBP (0.70 [0.49–0.91]), when HTN was defined as average 24-h SBP ≥ 125 mmHg. Moreover, the addition of standing to seated SBP (0.80 [0.68–0.92]) improved HTN detection when compared to seated SBP. These patterns were consistent for both the 2017 ACC/AHA and the 2023 ESH definitions for HTN. In summary, standing BP, alone or in combination with seated BP, outperformed seated BP alone in diagnosing HTN in adults. Office blood pressure (BP) measurement has been the most used method to characterize a patient’s BP load for many decades5. At present, all practice guidelines and consensus statements have recommended patients have office BP measured in a seated position when being screened for HTN and mention very little regarding taking BP in other positions such as supine or standing6. However, a recent meta-analysis investigating the accuracy of screening for HTN in U.S. adults revealed that the pooled sensitivity of office BP was only 54% with specificity of 90%, when taken in a single visit7. The low sensitivity of seated office BP measurements can result in misdiagnosis or delays in treatment, which may pose increased risk of cardiovascular complications. The limited accuracy of office BP in diagnosing HTN and predicting cardiovascular risk has led many guidelines to recommend out-of-office BP measurement, including home BP and 24-h ambulatory BP (ABPM) as diagnostic tools6. The advantage of 24-h BP monitoring over home BP monitoring is ability to capture BP load throughout the daytime and nighttime.Hypertension (HTN) is the main risk factor for cardiovascular disease (CVD) and effects approximately 46% of the U.S. population15. Moreover, the prevalence of OHT has been reported to be 1.2–2.6% in young-to-middle-aged adults, and the presence of OHT carries increased risk for development of overt HTN, increased risk of cardiovascular disease, and increased all-cause mortality20. Despite the increasing investigations into orthostatic BP, previous studies have not incorporated standing BP in the diagnosis of HTN. Accordingly, we performed an investigation in a group of adults free of cardiovascular disease and without anti-HTN medication use to determine if the addition of standing office BP to seated office BP would increase diagnostic accuracy for the presence of HTN.However, previous studies demonstrate that orthostatic hypotension (OH) and orthostatic hypertension (OHT) are associated with cardiovascular morbidity and mortality2, diabetes mellitus, pregnancy, history of substance abuse, or current smoker. As shown in Fig. All studies performed were approved by the Institutional Review Board at the University of Texas Southwestern Medical Center, all studies performed were in accordance with current guidelines/regulations, as appropriate, and written informed consent was obtained from all subjects. We retrospectively obtained participant data from the pool of subjects who have participated in clinical trials conducted in our hypertension research center. Studies were conducted in participants aged 18–80 years without previous history of HTN, cardiopulmonary disease, chronic kidney disease, use of anti-HTN medications, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 mSelf-reported variables included sex, race, and ethnicity. Body mass index (BMI), serum creatinine, fasting plasma glucose, eGFR, 24-h ABPM, seated and standing office BP were collected by research staff. Participants underwent a medical history and physical exam, and had BP measured in both seated and standing positions that was followed by obtaining a 24-h ABPM.23. Participants were fitted with the appropriate size BP cuff on the non-dominant arm. Monitors were initialized to define daytime as 0600–2159 h and nighttime as 2200–0559 h. Measurements were obtained every 20 min during the day and every 30 min at night. Duration of ambulatory monitoring was 24 h, and only patients with the minimum recommended number of ≥ 20 readings during the daytime period, and ≥ 7 readings during the nighttime period, and those with > 70% successful measurements, were considered acceptable, according to guidelines6.ABPM was conducted using validated Spacelabs model 90207 or 90227 monitors 1. Participants had been asked to refrain from caffeine, exercise, and smoking for at least 30 min before measurements. Seated measurements were performed 3 times sequentially (separated by 1 min). Standing office BP was measured immediately after seated office BP measurements had been taken, with participants arm supported on a table at heart level and measurements performed 3 times sequentially (separated by 1 min). The second and third readings of both seated and standing BP were averaged for analyses.Office BP was measured using a Welch Allyn Vital Signs 6000 series  oscillometric BP monitor. Participants were fitted with an appropriate size BP cuff on the non-dominant arm . All participants then had seated office BP taken after resting quietly for 5 min, with arm supported on a table at the level of the heart, back supported, both feet resting flat on the ground (uncrossed) and were instructed to stay silent during 5-min rest period prior to BP measurement, and during all sequential BP measurements, according to the current practice guidelines24. Participants were grouped by presence or absence of HTN as determined by the 2017 ACC/AHA HTN guidelines for average 24-h ABPM ≥ 125/75 mmHg, and by the 2023 ESH HTN guidelines for average 24-h ABPM ≥ 130/80 mmHg. These criteria were also used for calculating sensitivity and specificity of diagnostic tests as true HTN status. Validity measures of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with their corresponding 95% confidence intervals (CI). McNemar’s test was performed to assess the significance of the difference between sensitivity and specificity of standing and seated office BP for determining the presence of HTN.Statistical analyses were performed using SAS version 9.4. Participant characteristics are reported as mean ± standard deviation (SD) for continuous data and number  for categorical data. Office BP data had coefficient of variation additionally reported. Categorical variables were compared using the Fisher exact test or Chi-square when appropriated, and continuous variables were compared using two-sample T-test after checking normality. Predictors of standing and seated office BP were determined by multivariable linear regression analyses. All p-values were 2-tailed. A p-value < 0.05 was considered statistically significant. It was determined that a sample size of n = 122 would provide at least 80% power to detect a minimum sensitivity of 0.7 estimated from setting prevalence of HTN at 40% and 0.5 for the sensitivity of the null hypothesis25. The presence of HTN when determining the AUROC(s) was treated as binary under several established cut-offs termed “case definition” in the present study. The case definitions were defined as 24-h SBP ≥ 125 mmHg, 24-h DBP ≥ 75 mmHg, Daytime SBP ≥ 130 mmHg, Daytime DBP ≥ 80 mmHg, according to 2017 ACC/AHA guidelines, and 24-h SBP ≥ 130 mmHg, 24-h DBP ≥ 80 mmHg, Daytime SBP ≥ 135 mmHg, and Daytime DBP ≥ 85 mmHg, according to 2023 ESH guidelines6. Each case definition was used to sort participants into “case” and “control” groups based off each respective definition. These groups determined true presence of HTN, then the AUROC of seated and standing BPs was determined. Bayes factor (BF) was calculated on 5000 bootstrap samples and used to assess the significance of the difference between AUROC of seated and standing BP. Based on bootstrap samples, the number of times model A  outperforms model B  was divided by the number of times model B outperforms model A, to form the Bayes factor26. A Bayes factor of 3 or greater was considered a significant cutoff28. Sensitivity and specificity of seated BP was determined using the cut-offs of 130/80 mmHg, and 140/90 mmHg, according to most recent 2017 ACC/AHA, and 2023 ESH guidelines, respectively. There are no established cut-offs for diagnosing hypertension from standing BP. Therefore, we employed a statistical method known as Youden's Index, in conjunction with ABPM cut-offs (based on the 2017 ACC/AHA guidelines or the 2023 ESH guidelines), to identify the optimal cut-off points for standing SBP and DBP where the balance between sensitivity and specificity is maximized29.Overall diagnostic accuracy of seated and standing BP in diagnosing HTN was assessed using area under the receiver-operating-characteristic curve (AUROC)The participant characteristics of our cohort n = 125) are shown in Table 25 are shThe AUROC for standing office SBP (0.81 0.71–0.92]) was significantly higher than the AUROC for seated office SBP (0.70 [0.49–0.91]) in diagnosing HTN when case status was defined as having an average 24-h SBP ≥ 125 mmHg  was sigTo determine sensitivity, specificity, and predictive values of standing office BP, optimal cutoffs used were derived from Youden’s index from both average 24-h SBP/DBP ≥ 125/75 mmHg and daytime SBP/DBP ≥ 130/80 mmHg and found to be 123.5/80.5 and 123.5/81 mmHg, respectively. Therefore, when determining sensitivity and specificity of standing office BP according to the 2017 ACC/AHA HTN guidelines, we utilized the cut-off of 124/81 mmHg. For the 2023 ESH HTN guidelines, optimal cut-offs derived from Youden’s index for 24-h SBP/DBP ≥ 130/80 mmHg and daytime SBP/DBP ≥ 135/85 mmHg were found to be 123.5/83.5 and 133/81.5 mmHg, respectively. Thus, when determining sensitivity and specificity of standing office BP according to the 2023 ESH HTN guidelines, the cut-off of 123.5/83.5 mmHg (which corresponded to the average 24-h ABPM) was utilized. As shown in Table The new major findings in the present study investigating the utility of standing office BP measurement in detecting hypertension in young-to-middle-aged adults not taking anti-hypertensive medications were twofold. First, the diagnostic threshold for standing BP is consistent regardless of whether the definition for hypertension is based on average 24-h ambulatory BP ≥ 125/75 mmHg, or daytime ambulatory BP ≥ 130/80 mmHg. Second, we found that the addition of standing office BPs to seated office BPs enhances the diagnostic accuracy in detecting hypertension when compared to traditional seated office BPs alone and this finding was consistent for both the 2017 ACC/AHA and 2023 ESH definitions for hypertension, which provides further support for the validity of standing BP.7. Further, the meta-analysis reported that accuracy on a repeat office visit yielded a higher pooled sensitivity of 80% and a lower pooled specificity of 55% versus the initial visit based on 8 studies included 7. Our study found that on an initial screening visit, standing office SBP yielded a sensitivity of 71%, which is higher than the sensitivity of seated office SBP. Additionally, the AUROC of 0.81 found for standing office SBP further demonstrates excellent diagnostic performance and highlights that standing office BP has acceptable discriminative capabilities in identifying the presence of hypertension in adults. Our results also showed that the combination of seated and standing office BP resulted in greater discriminative capability to detect hypertension when compared to using seated office BP alone regardless of whether the 2017 ACC/AHA or 2023 ESH definitions for hypertension were used. Although the specificity is reduced to 67–70% when using standing BP measurement as a diagnostic tool, the specificity of standing BP in our study remains higher than the specificity reported in the meta-analysis when the second office BP measurement was conducted to confirm findings of the first office BP measurement7. Furthermore, the standing BP cut-off of 124/81 mmHg was remarkably similar whether average 24-h ambulatory BP or daytime ambulatory BP was used as the gold standard. Thus, routine standing BP measurement may facilitate diagnosis of hypertension more rapidly without additional office BP measurement to confirm a diagnosis.Results from a recent meta-analysis investigating the accuracy of hypertension screening in U.S. adults demonstrate the current accuracy of using traditional office BP methods during a single visit for the screening of hypertension yields a pooled sensitivity of 54% and a pooled specificity of 90% based on 15 studies included 14. Specifically, a recent analysis evaluating the change in BP to standing found that the presence of an increase in SBP of > 6.5 mmHg with standing was an independent predictor of major adverse cardiovascular events (MACE) in young-middle age healthy humans30. Moreover, the group that displayed “hyperreactivity”—the increased SBP to standing, had a higher prevalence of hypertension based on average 24-h ambulatory BP assessment in addition to the near two-fold increase in MACE [hazard ratio of 1.97 (95% CI 1.10–3.52)] based on a 17.2-year follow-up when compared with those with normal response in SBP to standing30. Excessive neurohormonal activation and sympathetic overactivity may be responsible for this observation30. Likewise, orthostatic hypotension, defined as a reduction in SBP of ≥ 20 or a reduction in DBP of ≥ 10 mmHg one minute after standing from a seated position, has also been shown to be associated with increased cardiovascular mortality33. Taken into context, our results highlight that by obtaining standing office BPs, a clinician can also utilize the advantage of increasing diagnostic accuracy for hypertension in addition to the important prognostic information provided.In addition to the improved diagnostic value that standing office BP provides, including an orthostatic BP assessment in an office visit can also inform the clinician of a patient’s future cardiovascular risk. Several prior studies have shown an association between increased standing office BP and cardiovascular morbidity and mortalityOur study is limited in that we only enrolled adults free of comorbidities who were not taking anti-hypertensive medications. Therefore, our results may not be applicable to patients with comorbidities or those on anti-hypertensive medications. Our study is retrospective in design and standing BP measurement was obtained only after seated BP, which does not allow randomization of the order of BP measurement in different positions. Nevertheless, standing BP measurement is almost always performed after seated BP in clinical settings. Despite these limitations, our study had several strengths. Our study protocol and essential findings are shown in Fig. In conclusion, our study is the first to demonstrate that obtaining standing office BP can increase sensitivity during an initial screening visit. Moreover, we show that the combination of both seated office BP and standing office BP performed better than seated office BP alone in detecting hypertension.The results of the present study have important clinical implications in the screening and diagnosis of hypertension. Our results suggest that obtaining standing office BPs during an initial screening visit provide a significant advantage through improving diagnostic ability and increase accuracy for detecting hypertension, thereby potentially reducing the need for a second office visit during the screening process. However, further studies are needed to determine the precise role of incorporating standing office BP in the overall diagnostic algorithm for the screening and treatment of hypertension.Supplementary Information.


Targeted education is crucial.•High BMI not linked to exams; hypertension in diabetics correlated with foot checks.•Patient education is key to preventing DFUs. Healthcare must prioritize foot protection and overall health. The prevention of diabetic foot ulcers (DFU) precedes treatment, in that early prevention significantly reduces the incidence of foot ulcers. The main objectives of this study were to examine the current prevalence of proactive foot ulcer examinations among diabetic patients and analyze influencing factors, in order to provide a scientific reference for the prevention of DFU in diabetic patients. The National Health and Nutrition Examination Survey (NHANES) 2011–2018 (n = 1278) data were utilized in this cross-sectional study. The dependent variable was whether patients underwent self-initiated foot ulcer inspections; risk factors that may lead to foot ulcers were included as independent variables. To explore the connection between the patient’s subjective motivation to inspect foot ulcers and risk variables, the weighted logistic regression model was further carried out. Among all risk factors, race, body mass index (BMI) and hypertension were statistically significant between whether patients were examined for foot ulcers or not. In the fully adjusted logistic regression model, only hypertension was positively correlated with diabetic patient-initiated examination for foot ulcers. This study suggests that there is still room for improvement in the knowledge and behavior of diabetic patients to be proactive in preventing DFU. Health care and community workers should conduct targeted training on diabetic foot prevention to reduce and prevent DFU by reinforcing knowledge to build positive attitudes and drive preventive behavior change. DiabeteDiabetic foot ulcer is one of the more serious vascular complications of diabetes, affecting roughly 6.3% of the world's population . DiabetiThe mechanisms underlying the development of foot ulcers in diabetic patients are complex and result from a combination of many intrinsic and extrinsic factors. Several major risk factors include: peripheral neuropathy, history of amputation or foot ulceration, foot deformity, peripheral vascular disease, visual impairment, renal disease, poor glycaemic control and smoking . The Wag2Previous research has played a pivotal role in advancing our understanding of factors influencing the prevalence of diabetic foot ulcers (DFU) among diabetic patients. Investigations into factors such as body mass index (BMI), income levels, and age have shed light on the complexities of DFU development. These studies have elucidated the significance of intrinsic and extrinsic factors that contribute to DFU risks.In the conventional theory of cognitive thought, there are differences in the perception of various items by age, gender, education level and even poverty status. Notably, the literature has indicated that the incidence of foot ulcers in diabetic patients increases with age, and is more common in males than females . StudiesEfforts have been directed towards elucidating the complex interplay between risk factors and preventive measures. By examining the multifaceted relationship between diabetic patients' demographic characteristics, clinical parameters, and proactive foot examination behavior, researchers have worked towards establishing a comprehensive framework for DFU prevention. As the understanding of DFU has evolved, researchers have sought to integrate these findings into actionable recommendations for healthcare professionals and patients alike. By combining empirical evidence with analytical insights, studies have endeavored to bridge the gap between research outcomes and real-world applications, ultimately contributing to the enhancement of clinical practice and patient care.3In this cross-sectional study, the correlation between risk factors associated with DFU and the proactive foot examination behavior of diabetic patients was investigated. The data for this cross-sectional study were gathered from the NHANES website (https://wwwn.cdc.gov/nchs/nhanes/Default.aspx), which was a nationally representative assessment of nutrition and health conditions in the United States. We analyzed the data from the last 4 cycles (2011–2018). All NHANES studies were conducted in accordance with the Declaration of Helsinki, all participants provided informed consent, and the National Center for Health Statistics (NCHS) Research Ethics Review Board authorized them.Inclusion and exclusion criteria were next established based on DFU-related risk factors and the presence of diabetes mellitus, and patients who met the criteria were screened for the study. Finally, utilizing a weighted logistic regression model as the decision mechanism, the correlation between risk factors associated with DFU and the proactive foot examination behavior of diabetic patients was explored, providing a scientific reference basis for the prevention of DFU among individuals with diabetes.44.1A total of 39,156 subjects were enrolled in 4 consecutive NHANES survey cycles covering the periods 2011–2018. There were 36,026 participants who were under 20 years old or did not have diabetes and did not have foot examination data in this study. Then, the participants who had no data on BMI, smoking behavior and other covariates were also eliminated, resulting in the final research population of 1,278. 4.2The dependent variable was assessed from the question, “How often {do you check your feet/does SP check (his/her) feet} for sores or irritations? Include times when checked by a family member or friend, but do not include times when checked by a doctor or other health professional.” This was then dichotomized as checking feet: yes (greater than1 times) or no (0 times).. Demographic characteristics were obtained from the NHANES Demographics Data and included age, sex, race and education level. Age was grouped as 20–49, 50–79, ≥80 years old; sex was classified as male and female; the ethnicity variable contains Non-Hispanic White, Non-Hispanic Black, Mexican American, Other/multiracial and Other Hispanic; the education level is categorized as Any College, High school and Less than High school. BMI (kg/m2) is divided into three levels, with < 25.0 considered healthy weight, 25.0–29.9 regarded as obese and ≥ 30.0 as overweight. Smoking status was categorized as never, former, and current. Glycated hemoglobin (HbA1C) is classified into three grades, ranging from < 5.75 as normal, 5.75–6.5 as re-diabetes and otherwise as abnormal. Other covariates included dyslipidemia, hypertension, walking limitations, diabetic retinopathy, renal failure, stroke and coronary heart disease, the details of which can be obtained at https://www.cdc.gov/nchs/nhanes/.The independent variables were chosen with reference to the extensive literature on selected risk factors for diabetic foot ulcers . Demogra4.3Due to the consideration that the NHANES survey oversampled participants, we integrated the sample weights created in the NHANES analysis. Descriptive statistics use weighted frequencies for categorical variables and medians and 95% confidence intervals for continuous variables to describe subjects. The logistic regression was performed to assess the association between risk factors and foot check after adjusting for potential confounding factors. Three models were built: an unadjusted model, a minimally adjusted model , and a fully adjusted model . A p-value < 0.05 (two-sided) was statistically significant.5The demographics and characteristics of participants with the foot ulcers examined in this study are presented in . We found a significant positive association between obese and foot examination and a significant negative association between overweight and foot examination in the unadjusted model (model 1). However, after adjustment for covariates, no significant associations were found for these models (models 2 and 3). Hypertension was positively associated with active foot examination in three models with statistically significant: model 1 , model 2 , model 3 .Based on these results, the logistic regression models between BMI, hypertension and whether the subject initiated a foot examination was analyzed separately . We foun6The findings of this study showed that approximately 80% of patients with a self-reported diagnosis of diabetes would have voluntarily examined their feet in the past eight years. Despite the relatively high proportion of patients with diabetes who initiate foot examinations, the proportion of patients without an active foot examination in the last 8 years is still quite high (17%). The study was conducted using NHANES data, a population-based survey, which represents the approximately 3.9 million people with diabetes with no active examination of their feet during the survey period. It is a worrying statistic showing the lack of awareness of foot ulcers among diabetics, leading to a multi-fold increase in the likelihood of foot ulcers being one of the most common clinical causes. Health care and community workers should provide targeted and individualized health education to patients with diabetes. Early identification and timely effective intervention of risk factors for DFU is essential for the management of DFU.In this study, we introduced age, sex, race, poverty status, education level, BMI, smoking, glycohemoglobin, dyslipidemia, hypertension, walking limitations, diabetic retinopathy, renal failure, stroke and coronary heart disease as risk factors associated with patient-initiated foot examinations, and calculated the proportion of each factor in the different populations, as well as analyzing the correlation with active foot examinations in diabetic patients. However, these risk factors  associated with the development of DFU in this study were not significantly different between diabetic patients who actively examined their feet and those who did not, suggesting that diabetic patients lack awareness of self-prevention of foot ulcers and have not yet realized the importance of effective assessment in the prevention of DFU.A significant correlation was found between the prevalence of disease and ethnic variability, particularly in diabetes, so that the occurrence of diabetic foot may also differ between ethnic groups . The corThis study revealed that foot ulcers are predominantly concentrated among diabetic patients. The study analysis revealed that diabetic patients with high blood pressure were more proactive in checking for foot ulcers, possibly because blood pressure measurements were more easily done on a regular basis. The patients are actively checking their feet for ulcers whenever their blood pressure increases. Nevertheless, in summary, elevated blood pressure is only one possible cause of DFU, and the convenience of checking blood pressure leads patients to focus only on blood pressure and thus ignore other causes. Therefore, the specialist medical staff should provide patients and their families with more forms and richer contents of education related to foot protection and strengthen health education on prevention of diabetic foot. In clinical practice, it is advisable for healthcare providers to pay special attention to hypertensive patients when treating individuals with diabetes and encourage them to actively engage in foot observation. Furthermore, in clinical settings, we emphasize that healthcare professionals need to take a comprehensive approach, advocating not only for proactive and vigilant foot observation but also addressing risk factors associated with foot ulcers, such as diabetes control, blood pressure management, and foot health. These health education measures enable patients to detect early prediabetic foot lesions, strengthen self-behavioral management and prevent the occurrence of ulcers.Additionally, this study invokes population data in the NHANES database of 2011–2018, which suffers from a short time period and an inadequate population base, and the awareness of DFU prevention among the population has now changed over time. In subsequent studies, we will extend the time period and increase the population base, and combine the clinical patient follow-up data to provide a scientific reference for the prevention of DFU.7We analyzed 1278 diabetic patients from the 2011–2018 cross-sectional study using NHANES data to uncover risk factors associated with promoting subjective examination of foot ulcers in diabetic patients. The results indicated that among the many risk factors, only hypertension was positively correlated with active examination of foot ulcers in diabetic patients. This study suggests that there is room for improvement in the knowledge and behavior of diabetic patients to proactively prevent DFU and that awareness of the potential risk factors for DFU needs to be increased so as to essentially reduce the incidence of DFU. Health care and community workers should conduct targeted training on diabetic foot prevention to reduce and prevent DFU by reinforcing knowledge to build positive attitudes and drive preventive behavior change.Xingkai Wang: Conceptualization, Formal analysis, Validation, Writing – original draft. Mengying Xu: Data curation, Investigation, Methodology. Lei Meng: Software, Visualization, Writing – original draft. Mingzhi Song: Methodology, Software. Zhuqiang Jia: Writing – original draft. Lin Zhao: Software. Xin Han: Visualization. Ming Lu: Project administration, Resources, Supervision, Writing – review & editing. Junwei Zong: Project administration, Resources, Supervision, Writing – review & editing. Shouyu Wang: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Through multivariable analysis, IL32 levels predicted both systolic blood pressure  and impaired blood pressure control  independently of demographic and metabolic confounders and of treatment. This study reveals that circulating IL32 levels are associated with impaired blood pressure control in individuals at risk of cardiovascular disease.Fatty liver disease is most frequently related to metabolic dysfunction (MAFLD) and associated comorbidities, heightening the risk of cardiovascular disease, and is associated with higher hepatic production of IL32, a cytokine linked with lipotoxicity and endothelial activation. The aim of this study was to examine the relationship between circulating IL32 concentration and blood pressure control in individuals with metabolic dysfunction at high risk of MAFLD. IL32 plasma levels were measured by ELISA in 948 individuals with metabolic dysfunction enrolled in the Liver-Bible-2021 cohort. Higher circulating IL32 levels were independently associated with systolic blood pressure (estimate +0.008 log Fatty liver disease affects roughly a quarter of the global population, is most frequently associated with metabolic dysfunction (MAFLD: metabolic dysfunction associated fatty liver disease) and is rapidly becoming a leading cause of advanced liver disease. Accumulation of neutral lipids within intracellular lipid droplets in hepatocytes is the hallmark of MAFLD , but proArterial hypertension, defined by persistently elevated blood pressure, is a major cardiovascular disease (CVD) risk factor, including heart failure and stroke, peripheral artery disease and chronic kidney disease (CKD). Arterial hypertension is a multifactorial disease, affecting up to 40% of the population and causing 7.7–10.4 million annual deaths worldwide ,10. DespWe recently identified Interleukin-32 (IL32) as the most upregulated transcript in the liver of obese individuals with severe fatty liver disease, namely, with steatohepatitis and/or clinically significant fibrosis. IL32 is an atypical multifaceted cytokine associated with several diseases and inflammatory conditions, mainly expressed by immune cells including natural killer (NK), monocytes and T-cells ,16,17. AOf note, IL32 has been reported to regulate endothelial cell function and activation, enhancing the expression of the intracellular adhesion molecule-1 (ICAM1)  in respoHere, we hypothesized that increased IL32 production triggered by hepatic fat accumulation and lipotoxicity may lead to endothelial activation and development of hyperntesion in individuals with metabolic risk factors. The aim of this study was, therefore, to examine the relationship between circulating IL32 concentration and blood pressure control in a cohort of individuals with metabolic dysfunction at high risk of MAFLD (the Liver-Bible-2021 cohort) with extensive adjustment for metabolic comorbidities. The clinical features of the 949 apparently healthy individuals with metabolic dysfunction included in the Liver-Bible-2021 are shown in 10 pg/mL among different individuals. In addition, in approximately one third of participants (31.4%) fasting IL32 levels were below the limit of detection (The distribution of baseline IL32 circulating levels is presented in etection .p = 5 × 10−9), with moderate accuracy (AUROC 0.75).Although in this cohort characterized by mild liver damage circulating IL32 was not significantly associated with liver stiffness , we confp = 0.049) and tended to be associated with a more favorable metabolic profile with lower abdominal circumference (p = 0.022), a trend for lower HbA1c (p = 0.051) and a Mediterranean dietary pattern . However, plasma levels of IL32 showed no association with circulating lipid or insulin levels. Furthermore, IL32 did not correlate with C reactive protein levels in 704 participants where data were available (p = 0.26). Impaired blood pressure control was associated with higher IL32 circulating levels . Furthermore, IL32 levels showed a significant association with systolic blood pressure , but not with diastolic blood pressure  and abdominal circumference  remained independently associated with circulating IL32. At the same time, both altered blood pressure control , and hypertension defined according to ESC guidelines  remained independently associated with circulating IL32.At multivariable analysis (p = 0.001) and, to some extent, systolic blood pressure  remained associated with higher levels of IL32.When considering IL32 tertiles distribution, in ordinal regression models, blood pressure control  and, to some extent, systolic blood pressure  remained associated with IL32 levels.When limiting the analysis to individuals with detectable circulating IL32, in generalized linear models, blood pressure control (estimate +0.079 logp < 0.05).The association of altered blood pressure control with IL32 was present both in participants with and without fatty liver . After s10 decrease in those treated, p = 0.0002). Among anti-hypertensive drugs, ACE-I, diuretics and beta-blockers were significantly associated with lower IL32 levels (p < 0.05). After adjustment for possible confounders  only ACE-I and diuretics remained independently associated with lower IL32 (p < 0.05).To corroborate the association between circulating IL32 levels and altered blood pressure, we analyzed the association between IL32 and the use of anti-hypertensive drugs. Overall, 254 participants were on anti-hypertensive treatments . Among those meeting the criteria for hypertension at presentation, 120 (12.6%) were on angiotensin converting enzyme inhibitors (ACE-I), 100 (10.5%) on angiotensin receptor blockers (ARB), 56 (5.9%) on diuretics, 49 (5.1%) on calcium antagonists, 31 (3.2%) on beta-blockers and 5 (0.5%) on alpha-blockers. The impact of anti-hypertensive medications on circulating IL32 levels are shown in p < 0.05). Systolic blood pressure as a quantitative trait was also independently associated with glucose control (HbA1c) and alcohol intake. Diastolic blood pressure was associated with BMI glucose control (HbA1c), alcohol intake, cholesterol and alcoholic drinks.The independent determinants of blood pressure levels and control are presented in p = 0.010) and altered blood pressure control (p = 0.0009) independently of all other covariates. Finally, circulating IL32 tended also to be independently associated with diastolic blood pressure, but the association was not statistically significant (p = 0.068).Importantly, higher circulating IL32 concentration was associated with both systolic blood pressure  with systolic blood pressure, both in healthy subjects and in the setting of chronic inflammatory diseases such as rheumatoid arthritis , supportIL32 is a multifunctional cytokine with pleiotropic effects and higher circulating IL32 levels were observed in a variety of diseases in which it amplifies inflammatory response, such as rheumatoid arthritis, systemic sclerosis, inflammatory bowel disease and several cancers, but also in coronary artery disease ,35,36,37Interestingly, in the present study cohort, the use of anti-hypertensive medications was negatively associated with circulating IL32, and treatment with ACE-I and beta-blockers was associated not only with improved blood pressure control in participants with hypertension, but also with lower levels of IL32. These data suggest that IL32 secretion may reflect endothelial damage and activation. Furthermore, IL32 may be involved in the pathogenesis of hypertension and possibly of the meta-inflammation leading to the progression of cardiovascular disease and its complications. Indeed, a protective anti-inflammatory activity of beta-blockers has previously been reported in patients with cardiovascular disease. In particular, beta-blocker initiation led to a decrease in circulating TNFα in patients with dilated cardiomyopathy , whereasThis study has some limitations. First, we measured IL32 at only one single time point for each individual after overnight fasting, and, thus, we could evaluate variations of IL32 that may occur over time and in response to metabolic cues. Furthermore, the diagnostic test employed was designed to detect a common IL32 region without the possibility to discriminate among the various isoforms. These are secreted by different cell types, which could not be assessed in the present study, and may possibly have opposite activity in the regulation of inflammatory pathways by different receptors , precludIn conclusion, our findings suggest that circulating IL32 levels are associated with systolic blood pressure control in individuals with metabolic dysfunction, whereas the use of anti-hypertensive medications reduces IL32. These results suggest that IL32 may be considered as a novel candidate therapeutic target to prevent cardiovascular disease in individuals with metabolic dysfunction. However, further studies are required to confirm these findings and to clarify the mechanism linking IL32 release, inflammation and hypertension.2), increased fasting glucose or type 2 diabetes (T2D) (fasting glucose ≥ 100 mg/dL), triglycerides ≥ 150 mg/dL, HDL < 45/55 in M/F, increased blood pressure (BP) values (systolic BP ≥ 130 mmHg and/or diastolic BP ≥ 85 mmHg at blood donation) or being on anti-hypertensive treatment. Part of this cohort has previously been described [The study was conducted in a cohort of apparently healthy individuals with metabolic dysfunction presenting for blood donation from June 2019 to February 2021 at the Transfusion Medicine unit of the Fondazione IRCCS Ca’ Granda Hospital (Liver-Bible-Cohort 2021). Participants aged between 40 and 65 years had to be willing to provide their consent, and have at least three of the following features associated with insulin resistance/metabolic dysfunction: overweight or obesity (Body mass index (BMI) ≥ 25 Kg/mescribed ,45. Indiescribed . The cliescribed .2. Conventional office BP at the time of donation was obtained. Patients remained seated comfortably in a quiet room for 5 min before beginning BP measurement and one BP measurement was recorded. A standard bladder cuff (12–13 cm wide and 35 cm long) was used. The cuff was positioned at the level of the heart, with the back and arm supported to avoid muscle contraction and isometric exercise-dependent increases in BP according to European Society of Cardiology (ESC) 2018 Guidelines [Weight and height were measured using standard procedures. Body mass index (BMI) was calculated as weight (kg)/height (m)idelines . Impaireidelines .Aminotransferases , high density lipoprotein (HDL), low density lipoprotein (LDL), cholesterol, triglycerides (TG), glucose and insulin were measured by standard laboratory methods at the Fondazione IRCCS Ca’ Granda core laboratory. The IL32-ALT-AST severe Fatty Liver Disease score was tested for the ability to predict non-invasively assessed fibrosing steatohepatitis .Liver stiffness measurement (LSM) and relative controlled attenuation parameter (CAP) were noninvasively assessed by vibration-controlled transient elastography (TE) with FibroScan  within 4 weeks of the presentation. According to EASL Clinical Practice Guidelines for non-invasive evaluation of liver disease, the following cut-offs were respectively used to indicate moderate/severe steatosis grade and advanced fibrosis: ≥275 dB/m for CAP (presence of fatty liver) and ≥8.0 kPa for LSM (presence of advanced liver fibrosis). Blood was drawn for evaluation in fasting conditions the morning of TE assessment. Fasting serum levels of alanine and aspartate aminotransferases (ALT and AST) were assessed by the IFCC 37 °C method. Fibrosis-4 (FIB-4), FibroScan-AST (FAST) and Fatty Liver Index (FLI) scores were calculated as previously reported ,50,51.g for 15 min and immediately stored at −80 °C at the Fondazione Biological Resource Center . Plasma samples were thawed only once and circulating levels of IL32 were quantified in duplicate using Human IL32 DuoSet ELISA kit  following the manufacturer’s instructions. The assay is designed to detect IL32α, IL32β and IL32γ with a detection range of 78.5–5000 pg/mL. Samples were diluted 1:2–1:20 in PBS and were measured in duplicate. Analyses were repeated for further dilution or no dilution when values outside scale were detected. Optical density was measured at 450 nm using TECAN infinite F200 PRO instrument . The minimal detectable concentration above blank was 39 pg/mL. When the IL32 concentration was not detectable, it was assumed to be 10 pg/mL [Blood samples were collected after an overnight fasting. For plasma collection, blood was centrifuged at 200× For descriptive statistics, categorical variables are shown as number and proportion. Continuous variables are shown as mean and standard deviation (SD) or median and interquartile range (IQR), as appropriate. Variables that were not normally distributed  were log-transformed before entering the analyses.p-values < 0.05 were considered statistically significant.To examine the variables associated with continuous traits, such as circulating IL32 levels, SBP and DBP, we used generalized linear models (GLM). Logistic regression (LR) models were fit to examine binary traits . To correct these associations for relevant confounders, we constructed a series of multivariable models adjusted for age, sex, ethnicity and clinical factors significantly associated at univariate analysis (selecting the most robust determinant in each category to avoid collinearity). Complete data were available for all patients included. Data were analyzed using the JMP software version 16 Pro . Performance for IL32-ALT-AST score to predicted noninvasively assessed fibrosing steatohepatitis was assessed by the area under the receiver operating characteristic curve (AUROC) in the Liver-Bible-2021 Cohort.The study design, analyses and results have been reported according to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines.


Central blood pressure (cBP) is known to be a better predictor of the damage caused by hypertension in comparison with peripheral blood pressure. During cardiac catheterization, we measured cBP in the ascending aorta with a fluid-filled guiding catheter (FF) in 75 patients and with a high-fidelity micromanometer tipped wire (FFR) in 20 patients. The wire was withdrawn into the brachial artery and aorto-brachial pulse wave velocity (abPWV) was calculated from the length of the pullback and the time delay between the ascending aorta and the brachial artery pulse waves by gating to the R-wave of the ECG for both measurements. In 23 patients, a cuff was inflated around the calf and an aorta-tibial pulse wave velocity (atPWV) was calculated from the distance between the cuff around the leg and the axillary notch and the time delay between the ascending aorta and the tibial pulse waves. Brachial BP was measured non-invasively and cBP was estimated using a new suprasystolic oscillometric technology. The mean differences between invasively measured cBP by FFR and non-invasive estimation were −0.4 ± 5.7 mmHg and by FF 5.4 ± 9.4 mmHg in 52 patients. Diastolic and mean cBP were both overestimated by oscillometry, with mean differences of −8.9 ± 5.5 mmHg and −6.4 ± 5.1 mmHg compared with the FFR and −10.6 ± 6.3 mmHg and −5.9 ± 6.2 mmHg with the FF. Non-invasive systolic cBP compared accurately with the high-fidelity FFR measurements, demonstrating a low bias (≤5 mmHg) and high precision (SD ≤ 8 mmHg). These criteria were not met when using the FF measurements. Invasively derived average Ao-brachial abPWV was 7.0 ± 1.4 m/s and that of Ao-tibial atPWV was 9.1 ± 1.8 m/s. Non-invasively estimated PWV based on the reflected wave transit time did not correlate with abPWV or with atPWV. In conclusion, we demonstrate the advantages of a novel method of validation for non-invasive cBP monitoring devices using acknowledged gold standard FFR wire transducers and the possibility to easily measure PWV during coronary angiography with the impact of cardiovascular risk factors. Systemic hypertension (HTN) is a major cardiovascular risk factor contributing to overall mortality and morbidity, affecting 35–40% of the population and resulting in up to 10 million deaths worldwide each year .The therapeutic reduction of HTN results in a decreased incidence of cardiovascular death, stroke, myocardial infarction, angina, and peripheral vascular disease .Routine non-invasive brachial artery blood pressure (BP) measurement is a fundamental step in HTN diagnosis management and therapeutic guidance. Cuff-based automated oscillometric measurement of brachial BP (bBP) in the clinicians’ office is the most widespread method of BP monitoring. The 2018 European Society of Cardiology (ESC) guidelines define HTN as office systolic BP (BPsys) values ≥ 140 mmHg and/or diastolic BP (BPdia) values ≥ 90 mmHg , whereasCentral (defined as aortic or carotid) blood pressure (cBP) measurements demonstrate superior clinical correlation with cardiovascular events  , as wellWhile arterial pressure varies constantly during the cardiac cycle, creating an arterial pressure wave, only systolic, mean, and diastolic pressures are routinely referenced. The pressure waveform also progressively changes along the arterial tree, and although mean and diastolic arterial pressures remain relatively constant, systolic pressure can increase by up to 40 mmHg between the aorta and the brachial artery . This vaAntihypertensive drugs show different effects on cBP as compared with bBP . CalciumHence, estimating cBP non-invasively in everyday practice is clinically attractive and might improve the diagnosis and management of HTN and clinical outcomes. Patients’ prognosis might also be improved through earlier and targeted screening of subpopulations at high risk of complications. To date, several cBP measuring devices are clinically available. Some use applanation tonometry of the radial artery and apply a mean transfer function to establish a central pressure curve ,17. We have shown the limited applicability of a generalized transfer function from radial recordings , while aAortic pulse wave velocity (PWV) measurement, although difficult to achieve, was recently suggested by the European Society of Hypertension/European Society of Cardiology guidelines as the gold standard for the assessment of aortic stiffness ,20. SeveValidation of new non-invasive cBP devices is most commonly performed by comparison with either a previously validated non-invasive method, which is suboptimal, or by comparison with invasive fluid-filled catheters (FF) . FF cathHigh fidelity micromanometer tipped wires are used clinically to assess the fractional flow reserve (FFR) in coronary arteries and are an appealing alternative to FF, offering an invasive measurement of the PWV between the ascending aorta and the brachial artery. The PWV, and arterial bed stiffness in total, might explain reported high differences between measured and estimated cBP . We sought to develop an accurate invasive reference method to validate new non-invasive devices measuring cBP and PWV using high-fidelity micromanometer tipped FFR wires for the measurement of cBP. The adoption of more precise and high-fidelity validation methods may improve the clinical practice of cBP monitoring, and improve the implementation of practice guidelines and clinical outcomes.We report on the first application of FFR coronary wires for invasive cBP validation in the assessment of the Uscom BP+  non-invasive cBP monitor. The BP+ measures cBP using a patent protected method based on brachial oscillometric pressure cuff measurements and applying a physics-based model of the left subclavian artery to brachial arterial branch to the low-frequency suprasystolic brachial artery pressure waveforms .The study protocol was approved by the Institutional Review Board at both Centre Hospitalier Universitaire (CHU) Ambroise Paré—Mons, and Hôpital Erasme—Brussels, Belgium (references B406201732846 and B4062021000294) and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients before the examination.Patients scheduled to undergo diagnostic cardiac catheterization and/or coronary angioplasty through the radial artery approach were enrolled . PatientUpon arrival to the catheterization laboratory, patients’ height and weight were noted. Left and right bBP were measured with the BP+ monitor to ensure minimal pressure difference between both arms and the absence of peripheral arterial disease. No sedative or premedication were used before or during the catheterization procedure. All routine medications were continued at the time of the procedure. After local injection of 2–3 mL of 1% lidocaine and successful placement of a 5Fr or 6Fr arterial sheath in the right or left radial artery, 5 mg of nicardipine were administered intra-arterially to prevent vasospasm during the procedure. Heparin (5000 U) was administered intravenously after insertion of the arterial catheter. The appropriate-size BP cuff was selected according to the manufacturer’s direction—24–32 cm or 32–42 cm—and was placed on the subject’s upper left arm with its lower edge 2.5 cm above the antecubital fossa.n = 75). The distal end of the catheter was positioned away from the walls of the aorta to avoid measurement interference from kinetic energy transfer. The natural frequency and the damping of the FF pressure system was measured on the bounce of oscillations during a fast flush test  5Fr or 6Fr Judkins Right catheter was stabilized in the ascending aorta, 2 cm above the aortic valve, under fluoroscopic guidance , fractional flow reserve was measured using a 0.014” wire including, at its tip, a high fidelity electronic pressure transducer  after additional Heparin (2500 U) was administered intravenously [When clinically indicated . Automatic batch analysis of all signals avoided intra-observer variations. Ten to twenty consecutive beats of the aortic and brachial pressure waves were averaged to limit the effect of physiological beat to beat variability  was calculated from the measured length of the pullback and the time delay between the ascending aorta and the brachial artery pulse wave foot estimated by the maximum upstroke of their second derivative, gating both measurements to the R-wave of the ECG . ®.On the digitalized signals, as well as on the iLab FFR monitor from Boston Scientific, we could visualize oscillations that were sometimes important on the FF catheter signals, associated with suboptimal damping as shown in Simultaneously, the Uscom BP+ was placed on the left arm to measure the reflected wave transit time (RWTT), which can estimate PWV using the jugulum to symphysis distance as PWV = 2 × jugulum-symphysis distance (m)/RWTT (s) . The tim® Statistics version 23 software .Bias and precision were determined using the Bland–Altman method  using SP2, with 67% male.Among the 75 patients studied, 52 patients were recruited for the comparison between the cBP and the FF catheter, and 20 of them had an additional comparison with the FFR wire when a fractional flow reserve (FFR) measurement was clinically indicated. Subjects’ characteristics are shown in 2; 74% of them were male.Aorto-tibial atPWV was measured in 23 additional patients who had a mean age of 60.4 ± 10.4 years and a BMI = 29.8 ± 4.3 kg/mThe mean differences between invasive FFR wire and non-invasive BP+ systolic, diastolic, and mean cBP were −0.4 ± 5.7 mmHg ; −8.9 ± 5.5 mmHg ; and −6.4 ± 5.1 mmHg , respectively . p = 0.253), while comparison of Uscom BP+ cBPsys with FF measures demonstrates a significant difference (p = 0.041).The mean differences between invasive FF measurements and non-invasive BP+ systolic, diastolic, and MAP cBP were 5.4 ± 9.4 mmHg , −10.6 ± 6.3 mmHg ; and −5.9 ± 6.2 , respectively. Linear regression comparing Uscom BP+ cBPsys and invasive FFR data show no statistical difference (p = 0.005). This leads to an overestimation of bBPsys when BP is high, and an underestimation of bBPsys when the BP is low. Comparing the same data with invasive FF catheter showed, for systolic and diastolic blood pressure, −1.0 ± 11.1 mmHg  and −10.8 ± 5.5 mmHg .Invasive FFR measurements were compared with the oscillometric bBP measurements. The mean differences between bBP systolic and diastolic were −2.2 ± 9.8 mmHg  and −7.9 ± 7.0 mmHg , respectively . On the 2 of 0.815 and a Pearson correlation factor ρ = 0.903 (p < 0.001) for cBPsys. For cBPmean, R2 was 0.949 with the Pearson correlation factor ρ = 0.974 (p < 0.001) and for cBPdia, R2 was 0.936 with the Pearson correlation factor ρ = 0.967 (p < 0.001).In the 20 subjects where an FFR wire was used, we analyzed the correlation between FFR and FF cBP measurements . Measurep = 0.116), while there was a statistically significant overestimation of cBPmean when abPWV was higher (p = 0.021)  was calculated in 20 patients. Two patients were excluded due to irregular RR intervals. Mean abPWV was found to be 7.2 ± 1.8 m/s. There was no statistically significant relationship between abPWV and cBPsys (= 0.021) . There w2 was 0.5 and the Pearson correlation factor was only 0.7, with unpredictable significant variations of up to 2 m/s in PWV, reflected by the significant  standard deviation of the mean QRS-aortic BP rise delay of 66.7 ms  measured in the last 23 patients recruited in this study was 9.1 ± 1.8 m/s. Exploring whether measurements of atPWV might be simplified using the ECG instead of an invasive aortic BP curve, we measured the time between the R-wave of the QRS and the foot of the aortic blood pressure wave. This mean time delay was 66.7 ± 18.5 ms. On average, the simplified PWV computed using the time between the QRS and the foot of the tibial BP minus 66.7 ms was 9.3 ± 2.1 m/s, apparently close to the invasive gold standard atPWV. However, the R 66.7 ms ; this re2 was 0.019 with a Pearson correlation factor ρ = −0.137 (p = 0.59). For RWTTf, R2 was 0.013 with a Pearson correlation factor ρ = −0.114 (p = 0.65) (Computed reflected wave transit time (RWTT) was obtained on the BP+ device and separated into RWTT peak and RWTT foot . Trachet = 0.65) .2 was 0.003 with a Pearson correlation factor ρ = −0.052 (p = 0.817). For RWTTf, R2 was 0.202 with a Pearson correlation factor ρ = 0.45 (p = 0.36)  .p = 0.44). CVRF included obesity (BMI > 30 kg/m2), active smoking (or stopped less than two years), hypertension history (>130/80 mmHg), diabetes mellitus type 1 or 2, dyslipidemia, chronic renal failure (stage ≥ 4: MDRD ≤ 30 mL/min), and a personal history of STEMI or NSTEMI.Patients with more than two cardiovascular risk factors (CVRF) demonstrated a trend for a 0.6 m/s higher PWV: the mean abPWV for patients with the ≤2 CVRF group was 6.8 m/s and for the ≥ 3 CVRF group was 7.4 m/s, but this difference was not statistically significant (p = 0.076). The mean differences of cBPmean estimation were −6.7 ± 5.6 mmHg and −5.7 ± 5.3 mmHg, respectively (p = 0.128). The mean differences of cBPdia estimation were −7.9 ± 5.6 mmHg and −9.3 ± 6.0 mmHg, respectively (p = 0.518)  .This study demonstrates the validation of a non-invasive oscillometric cBP device compared with measurements from a high-fidelity micromanometer tipped FFR catheter. The same method was applied to compare non-invasive oscillometric cBP measurements with the invasive, but less accurate, FF catheter.Our data suggest the BP+ device and its algorithm accurately measured cBPsys, while there was a trend to overestimate cBPdia and cBPmean. Our findings concur with the meta-analysis from Papaioannou TG et al. , in whicDespite the high reliability of BP+ cBPsys measurements in our study, we demonstrate an over-measurement of cBPdia by approximately 5 mmHg, in line with the report of Gotzmann et al., who found a similar discrepancy comparing cBP measured invasively with a FF catheter and two non-invasive devices, one measuring the brachial volume displacement waveform with a cuff inflated at a pressure below brachial diastolic BP and the other one using an oscillometric recording of the brachial artery and applying the concept of pulse waves harmonics and Fourier analysis. This underestimation of cBPsys using an FF catheter mirrored our findings, in which the FF catheter significantly underestimated cBPsys. However, by using high-fidelity FFR wires we achieved the recommended cBPsys criteria for accuracy . One canOur study demonstrates that the Uscom BP+ cBPsys measurements compared with the high-fidelity FFR catheter measurements were accurate and met ARTERY criteria with a mean difference of −0.4 ± 5.7 mmHg, exceeding both recommended mean values ≤ 5 mmHg and SD ≤ 8 mmHg . A previThe first and qualifying step for the measurement of an accurate cBP is the accurate measurement of a bBP under reproducible conditions. While the non-invasive mean bBPsys was accurate despite a wide SD measurement, the bBPdia and bBPmean did not achieve the level of accuracy recommended by the ARTERY according to SD and the mean criteria. This finding prompted the manufacturer to review the calculations for diastolic and mean bBP, and additional subjects are currently being recruited for this ongoing validation.p = 0.041), indicating an underestimation of the Uscom BP+ device as cBPsys increased, while cBPdia and cBPmean were found to be unaffected. A finding which may have been associated with inaccuracies in the FF catheter is that this trend was not found when using the pressure of the FFR wire as the reference. Moreover, we did not find an influence of the number of cardiovascular risk factors on the accuracy in the estimation of cBPsys  method appears to fail this target in our validation study. Our validation study confirms issues raised from numerical simulations in a model of the arterial tree . One of The normal respiratory variation in BP waves complicates accurate comparison of contemporaneous data samples and may limit the comparison of results .Measurement of the PWV is derived from the distance of the pull back of the guide wire. As the catheter is introduced via the aorta into the sinus of Valsalva, the normal anatomical architecture of the aortic arch and any degenerative tortuosity may alter the pullback measurement and lead to an overestimation of PWV.Methodologically, this study compares the accuracy of FF catheters and FFR wires for the calibration and validation of non-invasive cBP measurements. While FFR is acknowledged as a superior measure and this novel study demonstrated a superior agreement of Uscom BP+ cBP measures and FFR values, this in isolation does not disprove the accuracy of FF. Yet, we identified many factors that may affect the frequency response of a FF system and may limit its use for non-invasive BP device validation. The use of an FFR wire micromanometer is likely to be more accurate, and therefore requires fewer observations and patients for validation.There is an increasing interest in the non-invasive measurement of cBP due to its better prediction of cardiovascular events and the potential benefits of its routine adoption in the clinical environment . AccuracFinally, we demonstrated the difficulties of estimating PWV without invasive measurements, using a default value for aortic BP as well as PWV derived from the RWTT parameter. However, we described an easy and reliable method to measure invasive PWV, which could be used for all patients presenting for coronary angiography.


In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0–tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight , systolic blood pressure , and mGFR . To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.Sodium–glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure–response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure–response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC Sodium–glucose cotransporter-2 (SGLT2) inhibitors increase urinary glucose excretion and decrease body weight, blood pressure, and urinary albumin excretion ,2. ImporA generally accepted mechanism underlying the benefits on kidney outcomes of SGLT2 inhibitors is that these agents restore tubuloglomerular feedback and thereby reduce glomerular hyperfiltration through dilation of the efferent arteriole (in type 2 diabetes) or constriction of the afferent arteriole (in hyperfiltering type 1 diabetes) ,11. ThisDespite these clinical benefits at a population level, there is a large inter-individual variation in response to SGLT2 inhibitors, and, consequently, a considerable proportion of patients remain at increased risk of cardiovascular disease and progressive kidney function loss. The albuminuria-lowering response, an established surrogate endpoint for kidney disease progression in clinical trials, was unsatisfactory in approximately 20% of patients ,16. Furt2, urine albumin-to-creatinine ratio (UACR) > 300 mg/g, a cardiovascular event within 6 months before inclusion, and use of nonsteroid anti-inflammatory drugs or diuretics that could not be discontinued 3 months before and during the intervention period. The primary endpoints were changes in measured GFR (mGFR) and effective renal plasma flow (ERPF) from baseline to week 12 of treatment with dapagliflozin versus gliclazide. Secondary endpoints included changes in body weight, systolic blood pressure, fasting plasma glucose (FPG), HbA1c, and urinary glucose excretion (UGE), among others.Dapagliflozin exposure and response data were obtained from 24 participants in the dapagliflozin arm of the RED study  A. The st2, UACR > 300 mg/g, hypertension that could not be controlled other than with alpha-blockers and/or beta-blockers, chronic use of an SGLT2- or RAS inhibitor, use of nonsteroid anti-inflammatory drugs or diuretics that could not be discontinued during the study and a cardiovascular event within 6 months before inclusion. Study participants were randomized to four 1-week double-dummy treatment periods with placebo, losartan 50 mg/daily, empagliflozin 10 mg/daily or losartan 50 mg/daily, and empagliflozin 10 mg/daily with 4 weeks wash-out periods in between. At the end of every treatment period, mGFR and ERPF were assessed as primary endpoints. Secondary endpoints were, among others, body weight, systolic blood pressure, FPG, and UGE. For the current analysis, all participants in the RECOLAR study were included and data from the period in which they received a placebo were used as baseline values, and data from the period in which they received empagliflozin were used to assess exposure and response  B. The prresponse B.Both clinical studies were performed in accordance with the Declaration of Helsinki and Good Clinical Practice and the study protocols were approved by the local medical ethics committees. All participants signed written informed consent before any study-specific procedure commenced.In the RED study, pharmacokinetic measurements were performed on the 10 timed blood samples that were primarily taken for the kidney hemodynamic measurements at the end of the treatment period at week 12. Participants were instructed to take the last dose of dapagliflozin at 8 p.m. the evening before the study visit, and dapagliflozin plasma concentrations were determined in samples collected, according to protocol, between 12 h and 21 h after dosing. Plasma samples were stored at −80 °C until shipment to the Department of Clinical Pharmacy and Pharmacology of the University Medical Center in Groningen. Dapagliflozin analysis was performed using a validated liquid chromatography with tandem mass spectroscopy method  of 1 µg/L, intra-assay precision (coefficient of variation (CV)) of 1.1–13.7%, inter-assay precision of 0.0–1.6% and accuracy of 94.6–101.0%) [2 body surface area and adjusting the rate of 20% glucose infusion, with supplementary glucose infusion when plasma glucose levels decreased by >0.2 mmol/L in 5 min. In the RECOLAR study, the kidney hemodynamics were obtained at the end of all four treatment periods in every participant, in a fasted state. The measurements at the end of the period, in which participants took only a placebo, were defined as the reference, i.e., baseline, values, and the measurements at the end of the treatment period with empagliflozin and placebo as response values. In both studies, 24 h urine collections to quantitate glucose excretion were obtained the day before the visits for the kidney assessments. Fasting blood samples were drawn at the start of these visits and used to assess drug-induced change in glucose and HbA1c (RED study only). Systolic blood pressure was measured using an automated oscillometric device  at the brachial artery of the nondominant arm at the start of both visits. Measurements were performed in triplicate at 1- to 2-min intervals and the mean of the last two measurements was used. All participants were asked to adhere to a “normal” salt (9–12 g or 150–200 mmol per day) and protein (1.5–2.0 g/kg per day) intake the week before the kidney hemodynamic measurements.In both studies, mGFR and ERPF were, respectively, assessed by inulin or iohexol and para-aminohippuric acid clearances with timed blood and urine sampling as described previously ,23. The 0–tau,ss) at steady state, was estimated using non-compartmental analysis. The elimination rate constant and apparent volume of distribution were estimated from the individual natural log-transformed concentration-time profiles. Repeated linear regression analysis was performed on the last data points to determine the best fit of the curve through the terminal part of the curves, as assessed by the adjusted R2, by including at least three data points and provided the slope was negative. As pharmacokinetic samples were collected at a steady state, a correction for residual drug from the prior dose was conducted by subtracting concentration measurements by the estimated concentration at T = 24 h following first-order elimination kinetics. Based on the apparent volume of distribution and the elimination rate constant, apparent AUC0–tau,ss was obtained by dividing the drug dose by the individual clearance.The individual, apparent, plasma exposure to dapagliflozin and empagliflozin, defined as the area under the plasma curve during one dosing interval  and model comparison was based on an F-test.Associations between age, sex, body weight, eGFR, mGFR, UACR, serum albumin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALAT), and, if available, alkaline phosphatase (AF), and aspartate aminotransferase (ASAT), and plasma drug exposure were evaluated using linear regression analysis. Non-normally distributed variables, as assessed by visual inspection, were log-transformed with base 2 to better approximate a normal distribution. Variables with a Response variables of interest in both studies were body weight, systolic blood pressure, FPG, UGE, mGFR, ERPF and FF, and HbA1c additionally in the RED study. In the RED study, measurements performed at the baseline visit were used as baseline values and compared to the values at the end of the 12 weeks treatment period. In the RECOLAR study, the measurements at the end of the period in which participants used only placebo, were defined as baseline values and compared to the values at the end of the 1-week treatment period with empagliflozin (and placebo). Urinary glucose values were log-transformed with base 2 before analyses to approximate a normal distribution. Differences in the variables of interest between baseline and end of treatment visit were assessed using a linear mixed-effect model with a random intercept per individual and visit as a fixed effect. 0–tau,ss and response was assessed using linear mixed-effects models. In all exposure–response analyses, a log-transformation with base 2 of AUC0–tau,ss was applied to better approximate a normal distribution. Exposure to the drug was assumed to be zero at baseline. As the base model, a model with a random intercept per individual was fitted to the data. This model was compared to a random intercept model including apparent AUC0–au,ss as a fixed effect to assess whether exposure can explain inter-individual variation. Model comparison was performed using a likelihood ratio test and a p-value < 0.10 was considered a significant improvement in model performance. A t-test was performed to evaluate whether the fixed effect estimate of apparent AUC0–tau,ss was significantly different from zero. All linear mixed-effects models were fitted using full maximum-likelihood estimation in R version 3.6.3 using package nlme (version 3.1-144).The relationship between drug exposure in terms of apparent AUCThe baseline characteristics of the included participants are presented in 0–tau,ss after 10 mg dapagliflozin was 1153.1 µg/L*h (CV 81.8%).In total, 237 plasma samples were available for quantification of the dapagliflozin plasma concentration in 24 participants in the RED study. In one participant, all 10 dapagliflozin concentrations were below the LLOQ. This participant was excluded from the analysis due to poor study drug adherence. Two other samples were below LLOQ and excluded from the analysis, resulting in the inclusion of 225 dapagliflozin concentrations in the exposure analysis. The demographics of the 23 included participants are presented in 0–tau,ss was considered not reliable. The demographics of the 20 included participants are presented in 0–tau,ss after 10 mg empagliflozin was 2035.7 nmol/L*h (CV 48.4%).In total, 84 plasma samples were available for quantification of the empagliflozin plasma concentration in 21 of the 24 included subjects in the RECOLAR study. One subject was excluded from the pharmacokinetic analysis because no negative slope could be obtained in the non-compartmental analysis and therefore estimation of the apparent AUCp = 0.06), GGT , and ALAT  were associated with exposure in the univariate analysis (p = 0.13) (p = 0.007), eGFR , UACR , and serum albumin  were associated with exposure in the univariate analysis (p = 0.008), eGFR , and serum albumin  were associated with empagliflozin exposure  . For empanalysis . In the exposure .0–tau,ss was associated with an increase in UGE of 48.7% (p < 0.001), a decrease in body weight of 0.29 kg (p < 0.001), in systolic blood pressure of 0.80 mmHg (p = 0.002), in HbA1c of 0.51 mmol/mol (p < 0.001), in FPG of 0.09 mmol/L (p = 0.002), in mGFR of 0.83 mL/min (p = 0.03) and in FF of 0.09% (p = 0.04) (p = 0.06). For empagliflozin, it was estimated that every doubling of apparent AUC0–tau,ss was associated with an increase in UGE of 48.1% (p < 0.001), a decrease in body weight of 0.13 kg (p = 0.002), in systolic blood pressure of 0.65 mmHg (p = 0.045), in FPG of 0.16 mmol/L (p < 0.001) and in mGFR of 0.78 mL/min (p = 0.002) (p = 0.85) or FF  was observed  . No sign= 0.002) . No signobserved .In this post hoc analysis of two clinical studies with dapagliflozin and empagliflozin, we showed that both dapagliflozin and empagliflozin exposure is highly variable between patients with type 2 diabetes. The variation in systemic exposure to these SGLT2 inhibitors seems to be associated with clinical variables previously observed with SGLT2 inhibitor exposure including demographic, anthropomorphic, metabolic, kidney, and liver function variables.0–tau,ss compared to men. This is opposite to what has been previously reported [The inter-individual variation in plasma exposure to dapagliflozin and empagliflozin was high with a coefficient of variation of, respectively, 82% and 48%. For dapagliflozin, part of this variation was explained by sex, with women having an approximately 50% lower apparent AUCreported . We do nreported . Howeverreported ,26, but reported ,27. Furtreported . No effeExposure–response relationships for SGLT2 inhibitors have been well characterized for UGE and glycemic control, as primary efficacy variables, with higher exposure being consistently associated with a larger increase in UGE and decreases in FPG and HbA1c ,28,29,30This study shows that a lower exposure is associated with a poorer response and suggests that in non-responders to dapagliflozin or empagliflozin a higher exposure may be considered to improve the patient’s response. As only one dose level was tested in the current analysis, we cannot speculate on whether higher dosages lead to improved outcomes. For that, additional analysis should be performed, characterizing dose-exposure–response relationships for multiple dose levels. Despite exposure–response relationships between the RED and RECOLAR studies appearing to be similar, we do not recommend comparing these associations head-to-head due to important differences in the enrolled populations and study designs. In the RED study, 65% of the participants were using a RASi versus none in the RECOLAR study. Furthermore, the herein-reported kidney hemodynamics in the RED study were measured during euglycemic clamp while in the RECOLAR study in a fasted state, which complicates direct comparisons. Lastly, the treatment duration differed between the studies with a one-week treatment duration in RECOLAR and 12 weeks in RED. The hemodynamic response with SGLT2 inhibitors is fully present after one week of treatment as shown previously but one week of treatment is insufficient for a full response to body weight. This can also explain the smaller-than-expected body weight reduction with empagliflozin. Our study has several limitations, mostly related to the study populations. Both studies included relatively homogeneous populations, especially regarding body weight, liver, and kidney function. It is, therefore, possible that we could not identify the relationship between these variables and plasma drug exposure very accurately. In addition, no participants with CKD were included, which further limits the generalizability of the associations between GFR and exposure. Because few females were enrolled in both studies, the association between sex and dapagliflozin but not empagliflozin exposure should be interpreted in the context of low statistical power, and additional studies are required. Lastly, the actual times of drug intake and sample collection were not recorded; therefore, we must assume that this was undertaken as close to the protocol as possible.The plasma exposure to dapagliflozin and empagliflozin showed a large variation between patients and related to inter-individual variation in mGFR response as well as in response to several clinical variables.