The number of people living with type 2 diabetes (T2D) and its complications worldwide is increasing at an alarming rate. Fortunately, our understanding of the benefits of glucose-lowering agents from the sodium–glucose co-transporter-2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist classes on cardiovascular and kidney outcomes is advancing; this means we now have new options to mitigate the risks of these complications in patients with T2D. The SGLT2 inhibitors have consistently demonstrated benefits on atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and heart failure (HF) events in dedicated outcome trials. Large guidelines groups now recommend SGLT2 inhibitors as a standard of care in patients with T2D and comorbid ASCVD, CKD and/ or HF. Evolving evidence additionally indicates kidney and HF benefits of SGLT2 inhibitors in populations without diabetes. These agents likely provide heart and kidney benefits through multiple mechanisms, as their impact on heart and kidney outcomes cannot be fully explained by their direct metabolic effects. On-going work to elucidate the beneficial mechanisms at play with SGLT2 inhibitors will help further optimize these life-saving therapies in patients with and without T2D. Fortunately, recently completed cardiovascular and kidney outcomes trials have identified agents from the sodium–glucose co-transporter-2 (SGLT2) inhibitor and glucagon-like peptide-1 receptor agonist (GLP-1 RA) classes as having important benefits on cardiovascular, kidney and HF outcomes in patients with T2D. Accordingly, agents from these medication classes are recommended to improve glycaemic control, promote weight loss and mitigate heart and kidney risk in patients with T2D.8Over 37 million people in the USA live with diabetes mellitus, equating to over 11% of the population.This review discusses current evidence for use of SGLT2 inhibitors based upon available data from large cardiovascular outcome trials, and then discusses dedicated kidney and HF trials. We then briefly discuss the plausible biological mechanisms by which SGLT2 inhibitors convey heart and kidney protection. Additionally, we provide an overview of current clinical practice recommendations for the use of SGLT2 inhibitors to improve glycaemic, heart and kidney outcomes, and discuss important risk-mitigation strategies when initiating these therapies.9 The guidance was issued in the wake of cardiovascular safety concerns raised for the thiazolidinedione agent rosiglitazone,10 and called for cardiovascular safety and risk to be assessed thoroughly during drug development.9 Subsequently, large cardiovascular outcome trials have been conducted and published with medications from the SGLT2 inhibitor, GLP-1 RA and dipeptidyl peptidase-4 (DPP-4) classes. While designed primarily to demonstrate cardiovascular safety, many of the trials conducted with SGLT2 inhibitors and GLP-1 RAs have fortuitously demonstrated cardiovascular benefit relative to placebo, thus ushering in a new paradigm for the use of these agents to not only lower glucose, but to also modify cardiovascular risk.11 Results from large cardiovascular outcome trials have been reported for all four SGLT2 inhibitors currently marketed in the USA: canagliflozin, dapagliflozin, empagliflozin and ertugliflozin.15 Not only have these trials provided foundational knowledge substantiating the cardiovascular benefit of these agents in patients with T2D,15 importantly, they also included prespecified secondary outcomes that have prompted additional inquiry into the benefits of this class on both kidney and HF outcomes. These cardiovascular outcome trials for each agent are briefly summarized below, and in Table 1.In 2008, the US Food and Drug Administration (FDA) issued guidance to industry for the evaluation of cardiovascular risk with new glucose-lowering therapies.9 The programme comprised two integrated analyses – CANVAS (initiated in 2009) and CANVAS-Renal (initiated in 2014) – to assess the impact of canagliflozin on cardiovascular, kidney and safety outcomes in participants with T2D.12 The primary outcome for the CANVAS programme was a three-point major adverse cardiovascular event (MACE) outcome including of death from cardiovascular causes, non-fatal myocardial infarction (MI) or non-fatal stroke. Key secondary outcomes included progression of albuminuria, and a composite kidney outcome including sustained 40% reduction in estimated glomerular filtration rate (eGFR), kidney-replacement therapy and renal death.12The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program was one of the first cardiovascular outcome trial programmes initiated following the 2008 FDA guidance.12 Canagliflozin treatment was associated with a lower rate of MACE events compared with placebo , equating to a 14% risk reduction for the primary outcome .12 This finding supported the FDA’s granting an expanded indication for canagliflozin to reduce the risk for MACE in adults with T2D and established cardiovascular disease.16Over 10,000 participants with T2D and high cardiovascular risk were included in the trial and randomized to receive either canagliflozin or placebo.12 For canagliflozin-treated patients, risk was reduced for progression of albuminuria , as well as for the composite kidney outcome . In addition, the risk for HF hospitalization was reduced by 33% compared with placebo .12 Benefits observed on secondary kidney and HF outcomes were hypothesis generating, and supported dedicated investigation of canagliflozin in the CKD and HF settings.Benefits on key secondary outcomes were also observed.12 An additional unexpected finding was a two-fold increased event rate for amputations, primarily at the toe or metatarsal.12 This finding has raised questions on the general risk of amputation among patients using SGLT2 inhibitors, although any association is currently considered controversial and requires additional surveillance and study. While once included as a black box warning, a recommendation to consider factors that may increase the risk for amputation, including active infections or ulcers on the lower limbs, is now included as a warning in the US Prescribing Information for canagliflozin.16In terms of safety, participants receiving canagliflozin experienced adverse reactions generally associated with the class, including volume depletion-related events and genital mycotic infections.13 When compared with cardiovascular outcome trials for other SGLT2 inhibitors, DECLARE-TIMI 58 included a smaller fraction of participants with established ASCVD at baseline, representing a lower-risk population overall (Table 1). In this trial, the participants were randomized to receive either dapagliflozin or placebo. DECLARE-TIMI 58 included two primary outcomes: three-point MACE, and a cardiovascular composite outcome including cardiovascular death and HF hospitalization. Key prespecified secondary outcomes included all-cause mortality and a kidney composite outcome .13The Dapagliflozin Effect on Cardiovascular Events—Thrombosis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial was a large cardiovascular outcome trial that enrolled over 17,000 participants with T2D and existing atherosclerotic cardiovascular disease (ASCVD) or its risk factors.13 Dapagliflozin treatment did, however, reduce the risk for the co-primary outcome of cardiovascular death or HF hospitalization by 17% compared with placebo . This finding was primarily driven by benefit on HF hospitalization . Supporting the hypothesis of kidney benefit with dapagliflozin treatment, a benefit was observed relative to placebo for the kidney composite secondary outcome . Key safety findings reported in the DECLARE-TIMI 58 trial included increased event rates with dapagliflozin compared with placebo for diabetic ketoacidosis  and genital mycotic infections leading to treatment discontinuation and/or considered to be a serious adverse event . An increased risk for lower-limb amputations was not reported, although it was not included as an event of special interest in this trial.13After a median follow-up of 4.2 years, dapagliflozin was found to be non-inferior to placebo for three-point MACE .14 The primary outcome of the trial was a composite of death from cardiovascular disease, non-fatal MI and non-fatal stroke. The primary outcome occurred in 10.5% of participants in the empagliflozin group and 12.1% of participants in the placebo group .14 When examining components of the primary outcome, a 38% risk reduction for cardiovascular death and a 32% risk reduction for all-cause mortality was observed with empagliflozin.14 These findings supported the FDA’s granting empagliflozin an indication to reduce the risk of cardiovascular death in patients with T2D and established cardiovascular disease.18The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) assessed the impact of empagliflozin versus placebo on cardiovascular morbidity and mortality in participants with T2D and established cardiovascular disease.2 and/or urine albumin-to-creatinine ratio [UACR] >300 mg/g) found that empagliflozin treatment improved clinical outcomes and reduced mortality in this population.19 Participants receiving empagliflozin had a higher event rate for genital mycotic infections, but no increases in other adverse events relative to placebo were observed.14Analyses of EMPA-REG OUTCOME participants with CKD at baseline .15The Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV) is the only trial to date to have published outcomes with ertugliflozin.15 Additionally, an analysis of exploratory kidney outcomes suggested ertugliflozin treatment reduced the risk for a composite kidney outcome , and also preserved eGFR and reduced UACR.20 The most common adverse events noted during the trial were consistent with cardiovascular outcome trials for other SGLT2 inhibitors and included genital mycotic and urinary tract infections.15While ertugliflozin was not found to be superior to placebo for the primary outcome, several secondary and exploratory outcomes suggested a benefit of ertugliflozin treatment. Consistent with cardiovascular outcome trials for other SGLT2 inhibitors, ertugliflozin was associated with a reduction in risk for HF hospitalization versus placebo .Table 2).23Following the hypothesis-generating findings from cardiovascular outcome trials suggesting kidney benefits with SGLT2 inhibitors, several dedicated kidney outcome trials have been conducted to assess these potential benefits in detail. To date, full results are available from three dedicated kidney outcome trials with canagliflozin, dapagliflozin and sotagliflozin . The trial was stopped early following a planned interim analysis due to overwhelming efficacy. Risk for the primary kidneyspecific composite outcome  was reduced by 30% with canagliflozin treatment versus placebo. Canagliflozin also improved several cardiovascular composite outcomes compared with placebo, including composites of cardiovascular death or HF hospitalization , and of cardiovascular death, MI or stroke . The risk of HF hospitalization was also reduced with SGLT2 inhibition when compared with placebo .21The first of these to be published was the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial.22 Expanding on the findings from CREDENCE, DAPA-CKD enrolled patients with CKD and albuminuria (UACR ≥200 mg/g) with or without T2D (Table 2). As with CREDENCE, DAPA-CKD was also halted early following an Independent Data Monitoring Committee recommendation based on an overwhelming signal of benefit. The primary composite kidney outcome – a sustained decline in eGFR of at least 50%, progression to end-stage kidney disease or death from cardiovascular or renal causes – was significantly reduced with dapagliflozin treatment compared with placebo .22The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial similarly assessed the efficacy and safety of dapagliflozin versus placebo in patients with CKD.23 While sotagliflozin is not approved for use in the USA, the SCORED trial contributes to the growing body of evidence that SGLT2 inhibitors are beneficial for cardiovascular and kidney outcomes in patients with T2D and CKD. The trial was ended early due to loss of funding, and thus its primary outcome was changed to compare the total number of cardiovascular deaths, HF hospitalizations and urgent visits for HF between sotagliflozin and placebo (Table 2).23 With regard to kidney outcomes, a kidney composite secondary outcome  trended toward benefit for SGLT2 inhibition .23Results from the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial were reported in 2021.24 As with CREDENCE and DAPA-CKD, the trial was stopped early due to clear benefit during a planned interim analysis. EMPA-KIDNEY enrolled over 6,500 participants with CKD with or without T2D.26 Participants were included if they had an eGFR of ≥20 to <45 mL/min/1.73 m2 with or without albuminuria, or eGFR ≥45 to <90 mL/min/1.73 m2 with albuminuria (UACR ≥200 mg/g). Based on its inclusion criteria, EMPA-KIDNEY will provide important data on the impact of empagliflozin on kidney outcomes in patients with low eGFR and wide-ranging albuminuria. The primary outcome is a kidney composite including time to first occurrence of end-stage kidney disease, a sustained decline in eGFR to <10 mL/min/1.73 m2, sustained decline of ≥40% in eGFR from baseline, or cardiovascular or renal death.26While its full results have not been published at the time of this writing, high-level reported findings from The Study of Heart and Kidney Protection With Empagliflozin (EMPA-KIDNEY) have been positive.26 The benefits observed within these kidney outcome trials therefore demonstrate that SGLT2 inhibitors address residual risk for progression of kidney disease despite optimized ACE inhibitor or ARB treatment. For this reason, SGLT2 inhibitors are now considered standard of care for patients with T2D and CKD, as discussed in more detail later.Importantly, CREDENCE, DAPA-CKD and EMPA-KIDNEY all evaluated the effect of SGLT2 inhibitor treatment on top of standard-of-care angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy.Table 1 and Table 2). These findings have been substantiated by several large HF outcome trials published to date with dapagliflozin, sotagliflozin and empagliflozin (Table 3).31As discussed above, cardiovascular and kidney outcome trials with SGLT2 inhibitors have consistently reported benefits on HF outcomes  or cardiovascular death. The primary outcome occurred in 16.3% and 21.2% of participants in the dapagliflozin and placebo groups, respectively . Treatment with dapagliflozin was similarly beneficial in those with and without T2D.27The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial enrolled over 4,700 participants with New York Heart Association (NYHA) class II–IV HF and an ejection fraction ≤40%.29 Approximately half of participants in each treatment group (empagliflozin or placebo) had a baseline diagnosis of T2D. The primary outcome was a composite of cardiovascular death or hospitalization for worsening HF. The primary outcome occurred in 19.4% of participants in the empagliflozin group and in 24.7% of participants in the placebo group .29 Again, benefit for the primary outcome was consistent regardless of T2D status. The investigators also reported a decline in eGFR over the course of the trial, but with a slower annual decline among those treated with empagliflozin than those treated with placebo .29As did DAPA-HF, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial enrolled participants  with NYHA class II–IV HF and an ejection fraction ≤40%.30 Nearly 6,000 participants were enrolled in the trial, and less than half of them had T2D at baseline. The primary outcome was a composite of cardiovascular death or hospitalization for HF, and empagliflozin treatment significantly lowered the risk for the primary outcome compared with placebo . Adverse events reported more frequently in this population with SGLT2 inhibition than with placebo included genital mycotic infections, urinary tract infections and hypotension.30The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial expanded the investigation of SGLT2 inhibitors into a population with NYHA class II–IV HF with preserved ejection fraction (>40%).28 DELIVER reported a benefit of dapagliflozin therapy versus placebo on the primary composite outcome of worsening HF  or cardiovascular death .28Results from the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial provide additional evidence of benefit in patients with preserved ejection fraction.31 Participants enrolled in the trial had a diagnosis of T2D and were hospitalized and treated with intravenous diuretics for HF symptoms. The first dose of sotagliflozin or placebo was administered prior to hospital discharge in nearly 49% of participants, and to the rest a median of 2 days following discharge.31 The primary outcome was a composite that included cardiovascular death, and hospitalizations and urgent visits for HF. Sotagliflozin treatment decreased risk for the primary endpoint by 33% compared with placebo .31The Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) adds to the studies described above by assessing the impact of SGLT2 inhibition on HF outcomes in patients shortly following an episode of decompensated HF.Table 3 confirms that SGLT2 inhibitor therapy reduces the risk of cardiovascular death and HF hospitalization in a broad range of patients with HF.32 Based on their findings, the authors concluded that current evidence supports the foundational use of SGLT2 inhibitors to manage HF, irrespective of ejection fraction or care setting.32A recently published meta-analysis of the large HF outcome trials summarized in 39 It is a state of nutrient excess in which activation of nutrient-deprivation sensors is decreased, including sirtuin-1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK) and hypoxia-inducible factors .42 Suppressed activation of SIRT1 and AMPK contributes to the development of glomerular hyperfiltration, promotes mitochondrial dysfunction, oxidative stress and excess inflammation, and reduces autophagic clearance of damaged organelles.40 This suppressed SIRT1/AMPK signalling and resulting pro-inflammatory state, has deleterious effects on a variety of organ systems and contributes to the development of kidney and heart complications in diabetes.43T2D is associated with a chronic state of inflammation and measurable increases in markers of inflammation  and circulating immune cells.44 These structural changes subsequently lead to changes in ventricular function, altering the perfusion of tissues supplied by both small and large vessels.44 The altered metabolic state also contributes to impaired substrate switching and its resulting energetic deficits in the heart.45The pathogenesis of cardiovascular disease in T2D is driven by a multitude of factors. Metabolic, haemodynamic and inflammatory derangements result in cellular and functional changes in the myocardium. For example, dysfunction of the endothelium, progression of atherosclerosis, hypertrophy of cardiac myocytes and myocardial fibrosis are all key changes that are partly driven by inflammation in patients with T2D.47 Indeed, increases in inflammatory markers have been observed in the urine of patients with early T2D and nephropathy.49 Within kidney tissue, changes include infiltration of inflammatory cells and activation of resident T-cell populations.50 Up-regulation of pro-fibrotic cytokines further contributes to kidney fibrosis and destruction of the parenchyma.52 Matrix protein production is increased in kidney mesangial cells, compounded by a diminished breakdown of fibrotic proteins by matrix metalloproteinases.53The pathogenesis of CKD in T2D is likewise associated with metabolic and haemodynamic changes resulting from chronic inflammation, progressive kidney fibrosis and progressive eGFR decline. As previously noted, T2D is associated with an increased state of inflammation; oxidative stress and increased production of advanced glycation endproducts serve to activate the immune system early in the natural history of T2D.Figure 1).56 When used clinically, SGLT2 inhibitors are associated with reductions in glycaemia, weight and blood pressure, and with ketogenesis and erythrocytosis.54 The glycaemic effects of SGLT2 inhibition (the indication for which this class of medications was developed) do not fully account for the organ benefits of SGLT2 inhibitors observed in outcome trials, especially when considering the benefits in participants without diabetes that have been observed in several HF and kidney outcome trials.30 Further, evidence from large T2D trials suggests that intensifying glycaemic control does not notably reduce patients’ risk for major ASCVD events.59 Accordingly, the cardiovascular and kidney benefits observed in large outcome trials with SGLT2 inhibitors are not fully explained by their metabolic effects.SGLT2 inhibitors are proposed to mitigate heart and kidney risk through multiple mechanisms .54 It is driven by multiple factors including hyperglycaemia, hyperaminoacidaemia and increased proximal tubular reabsorption of sodium and glucose via SGLT2 and SGLT1 .54 Tubulo-glomerular feedback is a mechanism through which reabsorption of sodium and chloride in the macula densa promotes the release of adenosine , which then constricts the afferent arterioles in the glomerulus.54 Increased reabsorption of sodium and chloride in the proximal tubule diminishes the delivery of solutes to the macula densa, and consequently reduces adenosine production. This causes afferent arteriolar vasodilation, glomerular hyperperfusion and hyperfiltration within the glomerulus.60One likely mechanism of benefit of SGLT2 inhibition in the setting of CKD is by normalizing glomerular haemodynamics by restoring tubulo-glomerular feedback. Glomerular hyperfiltration is an early haemodynamic change observed in at least 40% of patients with T2D .54 In addition to their effects on tubulo-glomerular feedback, SGLT2 inhibitors also likely convey additional anti-inflammatory, anti-fibrotic, energetic and cardiac remodelling benefits that protect the heart and kidney .56 By inducing a biologic state that mimics starvation, SGLT2 inhibitors reduce nutrient excess signalling and help to reverse the cycle of glomerular hyperfiltration, inflammation and suppressed autophagy-mediated cytoprotection.42With use of SGLT2 inhibitors, solute delivery to the macula densa is restored by blocking the reabsorption of sodium chloride in the proximal tubule, thus restoring normal tubulo-glomerular feedback , recommend SGLT2 inhibitors as an option for patients not meeting individualized glycaemic goals to reduce hyperglycaemia and HbA1c.63 If a patient has one of these comorbidities, it is recommended to consider incorporating an agent with evidence of benefit into their medication regimen. Within the ADA Standards of Care, agents with ‘proven benefit’ are operationally defined as those with an expanded indication for improving ASCVD, HF or CKD outcomes (Table 4).65 Based on observed HF benefits in patients with and without T2D, the 2022 heart failure guidelines from the American Heart Association/ American College of Cardiology/Heart Failure Society of America recommend SGLT2 inhibitors within their treatment algorithm to improve HF outcomes.66When considering a glucose-lowering agent in a patient with T2D, the first recommended consideration per the 2022 ADA Standards of Care, and the European Association for the Study of Diabetes (EASD)/European Society of Cardiology (ESC) Consensus Statement is whether the patient has ASCVD, HF or CKD.67 For patients with T2D and CKD with albuminuria (e.g. creatinine ≥200 mg/g), the ADA preferentially recommends an SGLT2 inhibitor with primary evidence of reducing CKD progression.8 As previously discussed, both canagliflozin and dapagliflozin have demonstrated benefit in patients with T2D and CKD in dedicated kidney outcome trials, and are indicated for improving CKD outcomes;22 an indication to improve kidney outcomes is anticipated in the near future based on findings from the EMPAKidney trial.24For patients with T2D and CKD, use of an SGLT2 inhibitor is preferentially recommended by the ADA, EASD, American Association of Clinical Endocrinologists/American College of Endocrinology, ESC and Kidney Disease: Improving Global Outcomes (KDIGO).8 For patients with T2D and CKD (eGFR <60 mL/min/1.73 m2) who do not have albuminuria, the 2022 ADA Standards of Care state that either an SGLT2 inhibitor or GLP-1 RA with proven cardiovascular benefit can be used. These recommendations are based on the considerable cardiovascular-related morbidity and mortality risks that patients with CKD face.47If a SGLT2 inhibitor cannot be taken due to a contraindication or drug intolerance, the ADA recommends adding a GLP-1 RA with proven cardiovascular benefit.67 KDIGO recommends an SGLT2 inhibitor for patients with T2D and CKD (eGFR >20 mL/min/1.73 m2), irrespective of albuminuria, based on evidence suggesting that SGLT2 inhibitors confer consistent kidney and cardiovascular benefits irrespective of albuminuria.67KDIGO similarly recommends a first-line combination glucose-lowering regimen including metformin plus a SGLT2 inhibitor in patients with T2D and CKD, unless contraindicated.8 Risk mitigation strategies and patient counselling are thus important to maximize safety with the use of these agents (Table 5).67 A recent consensus report from the ADA and KDIGO notes that patients with T2D requiring insulin treatment are at particular risk for SGLT2-inhibitor-associated diabetic ketoacidosis; to mitigate the risks they suggest maintaining at least a low dose of insulin and considering holding SGLT2 inhibitor treatment during acute illness.68 Ketone screening can additionally be considered (Table 5).While the glycaemic, heart and kidney benefits of SGLT2 inhibitors are clear, it remains paramount that these medications are used safely: they are not without risks. SGLT2 inhibitors increase the risk for certain genito-urinary infections and associate with some less common adverse events (such as hypovolaemia–related events and euglycaemic diabetic ketoacidosis) that have been identified in clinical trials and in post-marketing surveillance.8 Furthermore, based on current guidelines, SGLT2 inhibitors should also be considered to improve HF outcomes in patients without T2D when clinically appropriate.In sum, a patient-centred approach should guide the selection of SGLT2 inhibitors for patients with and without T2D to improve cardiovascular and kidney outcomes, irrespective of HbA1c. Key considerations in the setting of T2D include 1) the risks of hypoglycaemia, ASCVD, CKD and HF; 2) the impact on body weight; 3) their costs and access; 4) their side effects and tolerability considerations; and 5) patient preference. Patients’ medication regimen and medication-taking behaviour should be re-evaluated regularly (every 3–6 months) and adjusted as needed to incorporate patient-specific factors that may impact the choice of treatment.Recommendations for using SGLT2 inhibitors in patients with and without T2D are evolving rapidly. As new data are published demonstrating the benefits of this drug class on heart and kidney outcomes, SGLT2 inhibitors are recommended not only as glucose-lowering agents, but also for their organ protective effects. They reduce risks for ASCVD, HF and CKD in the setting of T2D. Additionally, current data suggest the cardiovascular and kidney benefits of SGLT2 inhibition may extend to patients without T2D.SGLT2 inhibitors likely work through multiple mechanisms beyond their beneficial effects on glycaemia, blood pressure and body weight. Ultimately, SGLT2 inhibitors are now considered standard of care for patients with T2D and comorbid cardiovascular and kidney disease.


Out of 40 kidney biopsies, 2 were uninterpretable with inappropriate material and were divided into four subgroups based on their fibrosis percentage. Even though these elastography techniques were unable to differentiate between separate fibrosis stages, when predicting between the fibrosis and no-fibrosis group, we found a cut-off value of <20.77 kPa with the area under the curve (AUC) of 0.860, a p < 0.001 with 88.89% sensitivity, and a 75% specificity for the 2D SWE PLUS measures and a cut-off value of <2.8 Pa.s with an AUC of 0.792, a p < 0.001 with 94% sensitivity, and a 60% specificity for the Vi PLUS measures. We also found a cut-off value of <19.75 kPa for the 2D SWE PLUS measures  and a cut-off value of <1.28 Pa.s for the Vi PLUS measures  differentiating between patients with over 40% fibrosis and those with under 40%. We also discovered a positive correlation between the glomerular filtration rate (eGFR) and 2D-SWE PLUS values  and Vi PLUS values . C reactive protein (CRP) correlates with the Vi PLUS measures  but not with the 2D SWE PLUS measures . Conclusion: Our findings indicate that this novel elastography method can distinguish between individuals with different stages of renal fibrosis, correlate with the renal function and inflammation, and are easy to use and reproducible, but further research is needed for them to be employed routinely in clinical practice.Introduction: A renal biopsy represents the gold standard in the diagnosis, prognosis, and management of patients with glomerulonephritis. So far, non-invasive elastographic techniques have not confirmed their utility in replacing a biopsy; however, the new and improved software from Hologic Supersonic Mach 30 is a promising method for assessing the renal tissue’s stiffness and viscosity. We investigated whether this elastography technique could reveal renal tissue fibrosis in patients with chronic glomerulonephritis. Materials and methods: Two-dimensional-shear wave elastography (SWE) PLUS and viscosity plane-wave ultrasound (Vi PLUS) assessments were performed in 40 patients with chronic glomerulopathies before being referred for a renal biopsy. For each kidney, the mean values of five stiffness and viscosity measures were compared with the demographic, biological, and histopathological parameters of the patients. Results: In total, 26 men and 14 women with a mean age of 52.35 ± 15.54 years, a mean estimated glomerular filtration rate (eGFR) of 53.8 ± 35.49 mL/min/1.73m CKD has become a global public health problem with an increasing incidence and prevalence, resulting in a poor quality of life and high healthcare costs, and is linked to significant levels of mortality and cardiovascular morbidity, with leading causes such as diabetes mellitus, hypertension, and glomerulopathies ,2,3,4.The decline in the renal function is the consequence of tissue scarring and kidney parenchyma damage. Histopathology reveals that glomerulosclerosis, tubulointerstitial fibrosis, capillary loss, and tubular atrophy with the process of fibrosis are pathological conditions defined by the buildup and deposition of extracellular matrix constituents.Despite the increasing use of kidney biomarkers, fibrosis is evaluated solely by a kidney biopsy and a histopathological diagnosis continues to be the most significant diagnostic and prognostic method for this chronic renal illness. On the other hand, acute inflammatory activation is characterized by the abundance of neutrophils and macrophages, drawn and triggered by the cytokine production in injured tissue, which then stimulates the adaptive immune response; this aspect has also been cited as a crucial factor in the progression of fibrosis .By establishing appropriate therapy, an early renal biopsy may minimize the progression of CKD and, consequently, death ,7. HowevRecent years have witnessed the emergence of elastography as a non-invasive imagistic technique for identifying widespread disorders and this has boosted its usage in the medical community, particularly among gastroenterologists and endocrinologists ,10. The Because serum creatinine levels and eGFR are poor indicators of the severity of histological abnormalities in kidneys, a noninvasive test, that might provide an early diagnosis and/or prognosis to minimize the need for kidney biopsies and perhaps allow for early, targeted therapy, could improve patient care and survival. Up until now, even though kidney elastography research revealed an increased heterogeneity , multiplTherefore, the purpose of this study was to determine the viability of the ultrasound-based techniques provided by the Hologic Aixplorer Mach 30 system  and compare the results with the “gold standard” of a kidney biopsy in patients with chronic glomerulonephritis.In a tertiary nephrology department over a ten-month period (March 2022 to December 2022), cross-sectional, monocentric research was undertaken. Forty patients with chronic glomerulonephritis, who underwent elastography measures and then performed a renal biopsy, were included. In the Department of Nephrology Timisoara, Romania, the participants provided their informed consent and the study was conducted in line with the Declaration of Helsinki and was approved by our university’s ethical committee for research and institutional review board (41/4 March 2022).Out of each individual’s medical records, we collected the following information: their age, gender, height, weight, body mass index (BMI), kidney length, if they presented a history of hypertension or diabetes, as well as the following blood analysis: a complete blood count, urea, serum creatinine, sodium, potassium, uric acid, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), cholesterol, triglycerides, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and total bilirubin. The patients were also directed to provide urine samples for proteinuria/within 24 h and a urine culture.Before being referred for a renal biopsy, a single operator with five years of experience in renal ultrasonography performed elastography-based measurements on all individuals during the same session (F.-M.M), using the renal software comprising both 2D-SWE PLUS and Vi PLUS from the new Hologic Aixplorer Mach 30 ultrasound system .For each separate kidney, consecutive measurements were performed in the central section of the renal parenchyma, right under the subcapsular cortex, with the patient in dorsal decubitus immediately after voiding the bladder. Five consecutive measures of renal stiffness and viscosity were obtained at the same time without the knowledge of the patient’s medical history. The EFSUMB guidelines provide no quality criteria when performing kidney elastography, but considering the results of the majority of the published studies, we decided that the kidney’s stiffness should be reported as the mean value of 5 valid measurements.For each measurement (with the region of interest (ROI) selected by the renal software system to 10 mm and presented on the screen as a Q-box), the equipment software produced the following data, which are presented in A further improvement has been achieved by analyzing the raw data obtained from the elastography devices, as proposed by R. Barr et al. in 2020, and the new software from Hologic Aixplorer Mach 30 has more accurate and reliable renal stiffness information and uses more advanced processing techniques, represented as the 2D-SWE PLUS measures in kilopascal (kPa) .The 2D SWE PLUS measurements were carried out with a C6-1X convex transducer. The Young’s modulus (YM) of the ROI was calculated with the apparatus’ software utilizing the formula E = ρ × cs2 (E represents the tissue elasticity (in kPa), ρ is the tissue density (in kg/m3), and cs is the shear wave velocity measures in m/s). A quantitative map of the tissue’s stiffness is displayed using ultrafast imaging techniques, with a color scale spanning from dark blue to yellow then to dark red, corresponding to the YM values ranging from 0 to >50 kPa .Another feature of the new ultrasound device is Vi PLUS, which allows users to receive information on the tissue shear wave dispersion, that may be used to deduce the viscosity . Vi.PLUSThe kidneys’ stiffness would represent a non-invasive marker of fibrosis and the kidneys’ viscosity would represent a non-invasive marker of inflammation.After elastography, under ultrasonic guidance, a kidney biopsy was conducted in the right inferior pole of the kidney parenchyma with an 18G needle. The biopsy of the kidney tissue was collected and then fixed in 10% formalin before being sent for a histopathological investigation. Hematoxylin and eosin, periodic acid Schiff, Masson trichrome, Congo red, and silver stain were utilized to analyze the paraffin slices. The biopsy samples were sent to the same pathologist (A.V) with 10 years of experience to be examined by light microscopy; the pathologist was blinded to the clinical data of the patients. Based on the severity of interstitial fibrosis, the patients were divided into four categories: no/minimal fibrosis (0–10%) , mild fiThe biopsies were then examined using a semi-quantitative methodology, as was proposed by the Consensus Definitions for Glomerular Lesions by Light and Electron Microscopy: Recommendations from Working Group of the Renal Pathology Society by Hass et al., 2020  and the p-value of less than 0.05 was judged as being statistically significant. The areas under the receiver operating characteristic curves (AUC) were calculated for 2D SWE PLUS and Vi PLUS and offered as cut-off points that maximized the Youden index for recognizing fibrosis. Univariate and multivariate statistical analyses were also implied.For the statistical analysis, MedCalc Version 19.4  and Microsoft Office Excel 2019 were utilized (Microsoft for Windows). Using the Kolmogorov–Smirnov test, the distribution of the numerical variables was analyzed. Means and standard deviations are used to describe the variables with a normal distribution, whereas median values and ranges are used to represent the variables with a non-normal distribution. Percentages and numbers were utilized to illustrate the qualitative elements. Using the Pearson correlation coefficient, the relationships between the variables were expressed. A 2, and a mean proteinuria of 6.39 ± 7.42 g/24 h underwent elastography then renal biopsy procedures. No patient had a positive urine culture, but 8 had a history of diabetes, and 34 had a history of hypertension  of 26.71 ± 4.65, a mean kidney length of 104.33 ± 20.19 mm, a mean estimated glomerular filtration rate (eGFR) of 53.8 ± 35.49 mL/min/1.73 mrtension .p < 0.0001) and Vi PLUS measures .The mean 2D-SWE PLUS value for the whole group was 23.8 ± 7.45 kPa and the mean Vi PLUS value was 2.39 ± 0.73 Pa.s at a mean depth of measurement of 6.22 ± 1.43 cm. (p = 0.0085), hemoglobin (p = 0.0001), eGFR (p < 0.0001), urea (p < 0.0001), and Vi PLUS (p < 0.0001). However, in a multivariate regression model, only eGFR (p < 000.1) and Vi PLUS (p < 0.001) were independently associated with the 2D SWE PLUS measures (p < 0.0001).Univariate regression shows that 2D-SWE PLUS is influenced by cholesterol (p = 0.0020), CRP (p = 0.0189), eGFR (p = 0.0211), 2D-SWE PLUS (p < 0.0001), and urea (p = 0.0346). The multivariate regression model shows that only eGFR (p = 0.0067) and CRP (p = 0.0061) were independently associated with the Vi PLUS PLUS measures (p = 0.0016).Univariate regression shows that Vi PLUS is influenced by cholesterol : 20 patients, mild fibrosis (10–30%): 12 patients, moderate fibrosis (30–50%): 4 patients, and severe fibrosis (>50%): 2 patients; 2 patients were uninterpretable .p < 0.001 with 88.89% sensitivity, and a 75% specificity for the 2D SWE PLUS measures and a cut-off value of <2.8 Pa.s for detecting the presence of fibrosis with an AUC of 0.792, p < 0.001 with 94% sensitivity, and a 60% specificity for the Vi PLUS measures  and no-fibrosis group (0–10%), we found a cut-off value of <20.77 kPa for detecting the presence of fibrosis with the area under the curve (AUC) of 0.860, measures .p = 0.0001 with 100% sensitivity, and a 74.29% specificity) and a cut-off value of <1.28Pa.s for the Vi PLUS measures  differentiating between patients with over 40% fibrosis and those with under 40% , but neither of them correlated with age progression. In another study of our group in healthy participants, we found a mean kidney stiffness value of 31.88 ± 2.89 kPa and a mean viscosity value of 2.44 ± 0.57 Pa.s, and both correlated with eGFR and age . A possiNot all studies on kidney elastography demonstrate the same association between stiffness and histopathological alterations in the kidney. Most investigations comparing elastography with histological factors were conducted on patients with renal transplants ,28,29,30One research found no statistically significant association between kidney stiffness and the histopathological characteristics which were evaluated  . AdditioHu Q. et al., 2019  found, bOur findings clearly demonstrate a connection between reduced cortical stiffness and viscosity and the presence of fibrosis. The vast majority of earlier studies on native kidneys employed acoustic radiation force impulse technology and found as well significantly lower stiffness values in the CKD population utilizing biopsy, GFR, serum creatinine, and scintigraphy as indicators for a compromised renal function ,38.The 2D SWE PLUS and Vi PLUS methods were initially developed to identify liver fibrosis and inflammation ; the preNevertheless, despite the fact that renal elastography might be a promising method for monitoring the course of CKD, the research so far indicates that its heterogeneity is developed . The strSeveral limitations of our research should be acknowledged: the limited number of patients, the lack of an activity/chronicity index given the heterogenous etiologies of glomerulonephritis, the use of a standardized method, and quality criteria for performing elastography in kidneys.Our findings indicate that these novel elastography methods can distinguish between individuals with different stages of renal fibrosis, correlate with the renal function and inflammation, and they are easy to use and are reproducible, with a high patient acceptance, but further research is needed for them to be employed routinely in clinical practice.


We extracted patients and medical features from the electronic medical records (EMR), and the cohort was divided into a training/validation and testing data set to develop and validate the models on the basis of three algorithms: logistic regression (LR), random forest (RF), and extreme gradient boosting (XGBoost). We also applied an ensemble approach using soft voting classifier to classify the referral group. We used the area under the receiver operating characteristic curve (AUROC), precision, recall, and accuracy as the metrics to evaluate the performance. Shapley additive explanations (SHAP) values were used to evaluate the feature importance. The XGB model had higher accuracy and relatively higher precision in the referral group as compared with the LR and RF models, but LR and RF models had higher recall in the referral group. In general, the ensemble voting classifier had relatively higher accuracy, higher AUROC, and higher recall in the referral group as compared with the other three models. In addition, we found a more specific definition of the target improved the model performance in our study. In conclusion, we built a 6-month ML predictive model for the risk of rapidly progressive kidney disease. Early detection and then nephrology referral may facilitate appropriate management.Early detection of rapidly progressive kidney disease is key to improving the renal outcome and reducing complications in adult patients with type 2 diabetes mellitus (T2DM). We aimed to construct a 6-month machine learning (ML) predictive model for the risk of rapidly progressive kidney disease and the need for nephrology referral in adult patients with T2DM and an initial estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m Diabetes mellitus (DM) is a major cause of life expectancy reduction and premature death ,2,3. TheArtificial intelligence (AI) has been widely applied in medical fields for diagnostic assistance, outcome prediction, and guiding treatment. Machine learning (ML) is a subset of AI. ML models are algorithms that teach a computer to learn from data ,13. TherWe retrospectively extracted the electronic medical records (EMR) in our hospital from January 2008 to June 2021. Among them, we found 62,360 patients with a diagnosis of type 2 diabetes mellitus (T2DM) according to the International Classification of Diseases codes, and the inclusion criteria of our study were as follows: (1) hospitalized at least once with ICD-9 or ICD10 coding for T2DM, (2) at least two outpatient ICD-9 or ICD10 codings for T2DM, and (3) age at diagnosis of T2DM ≥ 20 years. The exclusion criteria were (1) patients who underwent dialysis before the diagnosis of T2DM and (2) renal transplant patients. Our study was approved by the institutional review board of Taichung Veterans General Hospital (IRB TCVGH No: SE22064A). Patient informed consent was waived because all protected health information was deidentified and the retrospective data analysis nature of this study. This research was funded by grants from the Ministry of Science and Technology of Taiwan (MOST 108-2314-B-005-005-MY3).All the extracted personal information of the patients was deidentified. The demographic features used for the machine learning models included age, sex, height, weight, and body mass index (BMI). The laboratory features include serum creatinine (Cr), blood urea nitrogen (BUN), fasting glucose, random glucose, glycated hemoglobin (HbA1c), spot urine protein to creatinine ratio (UPCR), spot urine albumin to creatinine ratio (UACR), hemoglobin (HGB), hematocrit (HCT), albumin, total protein, aspartate aminotransferase (AST), alanine transaminase (ALT), creatine phosphokinase (CPK), high-sensitivity C-reactive protein (hsCRP), serum sodium (Na), serum potassium (K), red blood count (RBC), white blood count (WBC), platelet, total bilirubin (Bil-T), uric acid (UA), total cholesterol (CHO), low-density lipoprotein (LDL), and triglyceride (TG). The comorbidities were extracted according to the ICD-9 or ICD-10 codes and included diabetic retinopathy, hypertension, coronary arterial disease (CAD), stroke, peripheral arterial disease (PAD), congestive heart failure (CHF), acute kidney injury (AKI), liver cirrhosis, cancer, bacteremia, sepsis, shock, peritonitis, ascites, and bleeding esophageal varices.2 and (2) the eGFR falling below 45 mL/min/1.73 m2. Clinical guidelines [2. However, a previous study showed a GFR < 45 mL/min/1.73 m2 at the time of referral is also a significant risk factor for mortality [2 to (1) GFR < 30 mL/min/1.73 m2 and (2) to <45 mL/min/1.73 m2.In this study, we aimed to construct multiple machine learning models to predict the risk of rapidly progressive kidney disease and the need for nephrology referral in diabetes patients. We compared two different prediction outcomes of renal function deterioration and the need for nephrology referral in diabetes patients : (1) theidelines ,20 recomortality . Hence, 2) at the target point and 90 days after the target point. We confirmed chronic kidney disease if the eGFR did not recover 90 days after the target point in the “referral” group. On the other hand, we labeled patients as being in the “non-referral” group if (1) the eGFR was persistently ≥ 30 mL/min/1.73 m2 at the target point and 90 days after the target point or (2) the eGFR was persistently ≥ 45 mL/min/1.73 m2 at the target point and 90 days after the target point. We further enrolled patients according to the criteria for the reference point as follows: (1) eGFR ≥ 60 mL/min/1.73 m2 at the reference point, (2) 180-day average eGFR ≥ 60 mL/min/1.73 m2 prior to the reference point, and (3) T2DM diagnosis before the reference point.We selected adult T2DM patients with pair eGFR records of a 180-day period between the reference point and prediction target point. We first determined the target point for each individual patient and then went back to determine the reference point to select patients who fitted the criteria for the reference point. We labeled patients as being in the “referral” group if the eGFR was persistently lower than our outcomes , random forest (RF), and extreme gradient boosting (XGBoost) to develop the predictive models. We further applied an ensemble approach using soft voting classifier to classify the referral group ,30. In tp < 0.05. Statistical analyses were performed using MedCalc for Windows, version 20.210 . The assessment of normality was conducted using the Kolmogorov–Smirnov test. The continuous variables with normal distribution are shown as mean ± standard deviation, whereas the continuous variables with non-normal distribution are presented as the median . The categorical variables are reported as numbers (percentage). Tests for the statistical significance were conducted using the chi-squared test for categorical variables and the Mann–Whitney test for non-parametric continuous variables. The level of significance was set at 2) to find the optimal method for this problem  as compared with experiment 1 (eGFR was persistently < 30 mL/min/1.73 m2). Proteinuria (UPCR or UACR) is also an important predictor for the risk of rapidly progressive kidney disease and the need for nephrology referral.2 at the reference point and a T2DM diagnosis before the reference point. We also labeled patients with only one laboratory result, showing an eGFR < 30 mL/min/1.73 m2 for experiment 1 and an eGFR < 45 mL/min/1.73 m2 for experiment 2 in this additional experiment. We did not confirm patients with a 180-day average eGFR ≥ 60 mL/min/1.73 m2 prior reference point and a persistently lower eGFR 90 days after the target point in this additional experiment. We conducted an additional experiment with loose inclusion and labeling criteria for both experiments 1 and 2. In this additional experiment, we included T2DM patients with one laboratory result showing an eGFR ≥ 60 mL/min/1.73 m2, and (2) diabetes patients should be referred to a physician experienced in the care of kidney disease for uncertainty about the etiology of kidney disease, difficult management issues, and rapidly progressive kidney disease [2 and <45 mL/min/1.73 m2 at the time of referral were powerful risk factors for mortality. Therefore, we performed one experiment with a predictive target of an eGFR < 30 mL/min/1.73 m2 and another one with a predictive target of eGFR < 45 mL/min/1.73 m2. In addition, our study design also predicted rapidly progressive kidney disease in a 6-month period. This is an important indication for nephrology referral in T2DM as well.Due to the heterogeneous phenotype of type 2 diabetic renal disease, the optimal time for the nephrology referral of T2DM patients is still challenging . The Ame disease . However disease  performeFew studies have focused on the prediction of diabetic nephropathy and renal function decline ,16,17,18Our result showed that the XGB model had higher accuracy and relatively higher precision in the referral group as compared with the LR and RF models, but LR and RF models had higher recall in the referral group. The lower precision means that the model had more false alarms, and the false alarms may increase the clinical load of the nephrologist. However, the higher recall may be more important for patient safety because it means that less patients who need nephrology referral (adult T2DM patients with rapidly progressive kidney disease) are neglected. In general, the ensemble voting classifier had relatively higher accuracy, higher AUROC, and higher recall in the referral group as compared with the other three models.Some potential limitations of this study should be acknowledged. First, the nature of the retrospective study may cause some unrecognized confounding factors to bias the findings. Second, we did not analyze the impact of medication in our study, and some medication may be associated with rapidly progressive kidney disease. Third, our study included a small sample size and was conducted at a single hospital. The majority of the population was Taiwanese. Fourth, the data set was highly unbalanced, despite our attempts to deal with this problem. Models trained on imbalanced data may cause the accuracy paradox. Precision and recall may be better metrics in such conditions. Fifth, we excluded patients with more than 12 missing features to deal with the missing data in the non-referral group and the imbalance of dataset, which may introduce bias in analysis. Sixth, only internal validation was performed in our study; external validation using a different data set is needed. Hence, further multicenter and multinational studies are required to confirm the stability of the performance of our predictive model.2. Our result showed that the XGB model had higher accuracy and relatively higher precision in the referral group as compared with the LR and RF models, but LR and RF models had higher recall in the referral group. In general, the ensemble voting classifier had relatively higher accuracy, higher AUROC, and higher recall in the referral group as compared with the other three models. Early detection of rapidly progressive kidney disease is key to improving the renal outcome and reducing complications in adult patients with T2DM.In conclusion, we built a 6-month machine learning predictive model for the risk of rapidly progressive kidney disease and the need for nephrology referral in adult patients with T2DM and an initial eGFR ≥ 60 mL/min/1.73 m


Sleep bruxism (SB) is a repetitive jaw muscle activity characterized by clenching or grinding of the teeth, which is classified under sleep-related movement disorders in the International Classification of Sleep Disorders—Third Edition. Because the potential common pathomechanism of SB and arterial hypertension is the activation of the sympathetic system as well as an increase in inflammatory factors, we aimed to examine the intensity of SB and the sleep architecture among patients with arterial hypertension. The study included a total of 91 Caucasian adult patients, among whom 31 had arterial hypertension diagnosed according to the current European Society of Cardiology/European Society of Hypertension (ESC/EHS) hypertension guidelines. The control group consisted of 61 normotensive patients. Patients with obstructive sleep apnea were excluded. A single full-night polysomnographic examination was conducted in the Sleep Laboratory, and then the results were analyzed based on the guidelines of the American Academy of Sleep Medicine. Bruxism episode index (BEI) was higher in the hypertensive group compared to normotensives. The groups also showed statistically significant differences in polysomnographic sleep indexes. Similar to BEI, arousal index, apnea–hypopnea index, and snoring were higher in hypertensives compared to normotensives. On the other hand, the mean and minimal oxygen saturation were lower in hypertensives compared to normotensives. A statistically significant positive correlation was observed between oxygen desaturation index and BEI in the hypertensive group, whereas this correlation was not statistically significant in the case of normotensives. In summary, nonapneic hypertensives had higher SB intensity, altered sleep architecture, decreased mean oxygen saturation, and increased snoring compared to normotensives. The results suggest that dental screening is necessary for patients with arterial hypertension, especially those presenting with the symptoms of SB. The definition and classification of bruxism have varied throughout the years. In 2013, Lobezzo first described bruxism as “a repetitive jaw muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible” .In 2018, an international bruxism consensus was published that clarified the previous definition along with further findings. The following definition clearly distinguishes SB from AB: “Sleep bruxism is a masticatory muscle activity during sleep that is characterized as rhythmic (phasic) or non-rhythmic (tonic) and is not a movement disorder or a sleep disorder in otherwise healthy individuals” . It was According to the latest research, SB is regulated centrally  and not peripherally  . One of Arterial hypertension is a prevalent condition that can increase the risk of heart, brain, kidney, and other diseases. It shares common pathophysiology with various sleep disturbances, such as obstructive sleep apnea (OSA) , restlesThe significance of dopamine and serotonin  gene altData on the relationship between arterial hypertension and SB are scarce. Moreover, the literature contains no studies based on polysomnography, which is a gold standard in the diagnosis of SB. Due to the fact that SB and arterial hypertension share the same pathomechanism, at least partially, we aimed to evaluate the intensity of SB and the sleep architecture among patients with arterial hypertension. In recent years, particular attention has been paid to the study of sleep architecture in arterial hypertension, as it has been proven that successive micro-arousals increase cardiovascular risk. Our study aims to bring attention to the patients with hypertension that could also affect the intensification of SB taking the common pathomechanism into consideration.The null hypothesis of the study was that hypertensives had increased SB intensity and altered sleep architecture. The scope of the study was to determine whether nonapneic patients with hypertension have altered sleep structures and different severity levels of bruxism compared to normotensives.n = 60) who had no medical history of hypertension and did not use antihypertensive medications; their blood pressure on admission was <140/90 mmHg. A sample size calculator was used to determine sample size. The calculator’s standard assumptions for our population were used: population size 3,000,000, fraction size 0.3, confidence level 0.95, and a maximum error of 10%. The required group size was 81. We recruited a group of 91 people, which is larger than required. The examination was carried out in the Sleep Laboratory of the Department and Clinic of Internal Medicine, Occupational Diseases, Hypertension, and Clinical Oncology at the Wroclaw Medical University, Poland. The study was approved by the Ethical Committee of Wroclaw Medical University (ID KB-407/2022). The trial was not registered in a WHO directory. The inclusion criteria were age over 18 years and willingness to provide written consent for the examination. The exclusion criteria were previously diagnosed sleeping disorder, secondary hypertension, past denervation of renal arteries, apnea–hypopnea index (AHI) > 10 in polysomnography, severe respiratory and cardiac failure, ischemic heart disease, diabetes, active neoplastic process, and neurological diseases as well as treatment with or addiction to analgesic drugs and/or drugs influencing muscle and breath functions, presence of severe mental disorders, active inflammation, and cognitive disability . Arithmetic means and standard deviations were calculated for quantitative variables, and percentages were calculated for qualitative variables. The distribution of variables was verified using the Shapiro–Wilk test. The hypotheses were tested with t-tests dedicated to unrelated and related variables, respectively. The differences between the mean values at a n = 91), 34% (n = 31) were hypertensives and 66% (n = 60) were normotensives (control group). The parameters determined in the polysomnography examination are included in p < 0.001). Furthermore, statistically significant differences were observed in total, phasic, tonic, and mixed bruxism episodes (The mean age of participants was 39.37 years. In the study group (episodes .p = 0.004). The mean AHI of hypertensive participants was 4.77 ± 2.85, while that of the control group was 2.01 ± 1.62 (p < 0.001).The studied groups also showed statistically significant differences in polysomnographic sleep indexes. The hypertensive group was characterized by a contrasting sleep architecture, with significant differences observed in the N2 sleep phase ; howeverp < 0.05), whereas it was not statistically significant in the case of normotensives  (An interesting correlation was found between oxygen desaturation index (ODI) and BEI in both studied groups. In the hypertensive group, this correlation was statistically significant  .2), minimal SpO2, and % of sleep with saturation of oxygen (SatO2) < 90%. All these parameters were found to be decreased in hypertensives compared to normotensives, while ODI was higher in hypertensives. Interestingly, no statistically significant difference in mean heart rate  was noted between the two groups  of hypertensive patients in comparison to normotensives. The study excluded patients with diagnosed OSA, which may influence sleep structure as well as blood pressure. We found that BEI was higher among patients with diagnosed hypertension compared to normotensives. This may be due to the fact that both SB and hypertension share a common pathomechanism, i.e., activation of sympathetic activity and increase in inflammation factors, as previously discovered by Michalek-Zrąbkowska et al. [To our best knowledge, this study is the first to use polysomnography, which is a gold standard in the diagnostics of SB, to analyze a large number (a et al. . The stua et al. . These aIn an earlier study, Nashed et al. examined 10 patients with SB and 9 patients without SB and investigated the changes in blood pressure . Their s2, and higher SpO2 < 90%, constitutes an independent risk factor for increased BEI [On the other hand, hypertension, as well as higher body mass index, lower mean SpOased BEI . MartynoIn summary, the correlation between arterial hypertension and SB remains unclear. Further research is needed to understand whether hypertension is an outcome of SB or if SB leads to the development of hypertension. It can be assumed that age plays a role. Among young adults, bruxism episodes may cause changes in blood pressure, which may predispose to the development of arterial hypertension, as indicated by Nashed et al. and Michalek-Zrabkowska et al. ,19. On tMoreover, as far as we know, the prevalence of SB decreases with age; therefore, research should be performed on an older hypertensive group with increased BEI to understand the features and consequences of SB events ,28.Patients with OSA were excluded from the present study because OSA is a risk factor for SB and may have influenced the results of examination ,30. It hOne of the most important findings of the present study is increased ArI in hypertensives compared to controls. Recently, Zhao et al. also showed an association between ArI and the prevalence of hypertension .Studies have indicated that increased heart rate is associated with microarousals which in turn are accompanied by increased sympathetic activity and decreased parasympathetic activity . MicroarIt is important to link SB with hypertension to ensure an early diagnosis and optimal treatment to prevent the long-term health consequences of cardiac events . PatientMoreover, symptoms presented by patients with hypertension such as headaches and tinnitus could indeed be symptoms of SB ,45,46.2 and increased snoring. Oxygen desaturation plays a controversial role in the development of SB [Early examination of SB is critical, as it is classified as a sleeping disorder accompanied by elevated inflammatory parameters , which cnt of SB ,47. Suzunt of SB . Neverthnt of SB ,47. The The oxygen desaturation index was indeed higher among the hypertensives group, and that can be explained by the fact that hypertensive patients have also other causes of presenting the desaturation, such as increased number of respiratory events or higher body mass index. Taking the heart rate into consideration, there are many more other compounds affecting this parameter such as increased sympathetic activity, age, other medical conditions, medications, diet, fitness level, and psychological factors.2 and more snoring episodes throughout the night. Further research is needed to study the pathophysiology of bruxism in patients with arterial hypertension together with an analysis of upper airway obstruction.Increased snoring can be explained by the fact that the obstructive process begins to occur in respiratory airways in patients with hypertension. In addition, hypertension is associated with altered metabolic pathways, which may result in overweight and consequently obstruction in the upper airways leading to lower SpOIn this study, a limitation was the fact that the patients did not perform automatic blood pressure measurement. It would be interesting to analyze the correlations between arterial blood pressure parameters and SB; however, it was beyond the scope of this study.What is more, the study group representing hypertensive patients consisted of 14 men and 17 women, whereas the control group was mostly represented by women, and this is an evident limitation of this research. Additionally, BMI was not evaluated in both groups, although it plays a very important role as a risk factor for high blood pressure and limits the research. We have not assessed temporomandibular issues in the study either.A limitation of the study was that patients spent only one night in the Sleep Laboratory for the polysomnographic examination. Examination for two or more nights would have given us more reliable information. An adaptive night is indeed very important, but due to the state of Polish healthcare, a longer stay for the research was unfortunately not possible.Nonapneic hypertensives had higher SB intensity, altered sleep architecture, increased snoring, and decreased mean oxygen saturation compared to normotensives.The association between oxygen desaturations and bruxism episodes exists only in hypertensives, but not in normotensives.Dental screening is necessary for patients with arterial hypertension, especially those presenting with the symptoms of SB.


The magnitude and nature of putative changes in longitudinal motion of the arterial wall in response to physical activity in humans remain unknown. The aim of this study was therefore to study the longitudinal motion of the carotid artery wall during physical activity in healthy humans. Using in‐house developed non‐invasive ultrasonic methods, the longitudinal motion of the intima‐media complex and the diameter changes of the right common carotid artery (CCA) in 40 healthy volunteers  were assessed at rest and during submaximal supine bicycle exercise. In a subset of the subjects (n = 18) also intramural shear strain were analyzed. The longitudinal motion of the intima‐media complex underwent marked changes in response to physical activity, already at low workload; with most evident a marked increase of the first antegrade displacement (p < 0.001) in early systole. Likewise, the corresponding shear strain also increased significantly (p = 0.004). The increase in longitudinal motion showed significant correlation to increase in blood pressure, but not to blood flow velocity or wall shear stress. In conclusion, physical activity markedly influences the longitudinal motion of the carotid artery wall in healthy humans already at low load. A possible “cushioning” function as well as possible implications for the function of the vasa vasorum, endothelium, and smooth muscle cells and extracellular matrix of the media, are discussed.The longitudinal motion of the arterial wall, that is, the displacement of the arterial wall  The longitudinal motion of the arterial wall, that is, the displacement of the arterial wall along the artery, parallel to blood flow, is still largely unexplored. Using in‐house developed non‐invasive ultrasonic methods we show, for the first time, that physical activity markedly influences the longitudinal motion of the carotid artery wall in healthy humans already at low load. Possible implications for cardiovascular function are discussed. Arterial wall motion measurements during physical activity are a challenging task. To remove low frequency movements of the upper part of the body caused by breathing an averaging algorithm was also developed and evaluated.22.1The experiments were performed on 40 healthy subjects . None of the subjects reported previous cardiopulmonary disease, diabetes or smoking, and all were free from current medication (inclusion criteria). Blood pressure at rest >140/90 at the examination was an exclusion criterion (the study was performed in 2015 using the definition of hypertension at that time). The Ethics Committee, Lund University, approved the study protocol and written informed consent was obtained from all subjects before the study.2.2The influence of exercise was studied using a supine bicycle  at an initial workload of 30 W with 20 W increases in resistance at 2‐min intervals. ECG was monitored continuously. In addition, auscultatory blood pressure was measured in the left upper arm at rest and at each level of exercise (see below), as well as every minute during at least 5 min after exercise was finished. The Borg Scale Borg,  for ratiThe subjects were positioned on the supine bicycle, the equipment for blood pressure and heart frequency measurements were applied, and the subject was familiarized with supine cycling. The subject then had to rest for at least 10 min on the bike . The room was kept quiet. Room temperature was kept at 21–23°C.After at least 10 min of rest (see above) ultrasound registrations of the right common carotid artery were performed (baseline). Four consecutive registrations of about 5 s were recorded . Immediately after, the peak systolic velocity in the CCA was recorded using pulse wave Doppler, and at the same time auscultatory blood pressure was measured. To ensure reproducibility of images at all stages of exercise, the position of the ultrasound transducer during baseline assessment was marked on the participant's neck. This enabled rapid identification of the same site of the common carotid artery to be imaged during and after exercise.After the initial rest, the subject started biking at an initial workload of 30 W. During the end of the last minute at each level of workload the participant were asked to stop biking for about 10 s  and ultrasound recordings of the carotid artery were performed (one‐two registrations of about 5 s), immediately followed by Doppler recordings of the blood flow velocity at the same site. At the same time as the ultrasound recordings were performed auscultatory blood pressure was measured. Then the participant was told to continue biking, and the workload was step wise increased 20 W until the desired degree of exertion was reached (see above). Breathing was not halted during the measurements. The participant then had to rest on the bike and ultrasound and Doppler registrations of the carotid artery, as well as blood pressure measurements, were again performed every minute during at least 5 min.%), was calculated based on the age‐predicted heart rate maximum , equipped with a 38 mm 3–12 MHz linear array transducer (L12‐3). The measurements were performed on the right common carotid artery approximately 2 cm proximal to the carotid bifurcation. The artery was scanned in the longitudinal direction, oriented horizontally in the image  of the adventitial region, as well as the minimum lumen diameter (at end‐diastole), distension and intima‐media thickness (IMT) were automatically measured using an in‐house developed image analysis software based on Nilsson et al., phase in the context relates to the signals time domain phase and differs from its denotation in other parts of this paper): First, the longitudinal motion curve was differentiated, and Hilbert transformed into a complex signal. The timing of end‐diastole in each cardiac cycle was identified using the diameter curve. These locations were then used to divide the complex longitudinal movement curve into equally long cardiac cycles. Then, the average phase shift (APS) between each cardiac cycle and all others was calculated using Equation Ck is the k:th out of N cardiac cycles, M is the number of samples used in a cardiac cycle and “^” denotes the conjugate. To improve stability, only the systolic part of the cardiac cycle was used for the APS. Each (full) cardiac cycle was then phase shifted with its corresponding APS. All cardiac cycles were averaged before calculating the real part. Finally, the resulting longitudinal motion was obtained by taking the cumulative sum of this average. Also, to remove drift, since the acquisition did not start and end at the same phase of the breathing cycle, a fitted straight line was subtracted from the result. This averaging procedure also suppresses erroneous motion that do not occur at the same time in every cardiac cycle.Breathing introduces a global low frequency movement of the upper part of the body that overlayed the longitudinal motion of the arterial wall Figure . To enabIn the averaged longitudinal movement curve different phases of longitudinal displacement were identified and measured as recently described  was measured/calculated. Arterial strain (AS) was defined as:P is auscultatory blood pressure.Further, the distensibility of the arterial was estimated and expressed as the distensibility coefficient DC defined as:sys) was measured at rest and at each workload (see above) using pulse wave Doppler (the peak Doppler envelope). The wall shear stress (WSS) was estimated using vsys and dsys using Equation 2.Also, the CCA peak systolic velocity  at rest, both during normal breathing and when the subjects have gently stopped breathing for a few seconds. The agreement was evaluated by estimating intraclass correlation coefficient  . Relationships between variables were assessed by Spearman rank order correlation coefficient and, in some cases, Pearson's product moment correlation, using MATLAB (The MathWorks Inc.). p < 0.05 was taken as significant.Data are presented as the mean value ± SD, unless otherwise stated. Independent samples 33.1p ≤ 0.001 and p = 0.004) in the older age group than in the young. Further, CCA strain (the relative diameter change) was lower in the older age group than in the young (p = 0.001). Further, as expected, the distensibility coefficient (DC) was lower and IMT was larger in the older age‐group than in the young . In addition, CCA peak systolic velocity was significantly higher in the young than in the older age‐group (p ≤ 0.001). The CCA end‐diastolic diameter did not significantly differ between the young and older age‐group .Clinical characteristics and measurements at baseline, that is, at rest before the bicycle was started are presented in Table 3.1.1At baseline, that is, at rest before the bicycle was started, a distinct complex bidirectional multiphasic longitudinal motion of the intima‐media complex of the carotid artery was seen in all subjects during the cardiac cycle. As previously reported  in the older age group, whereas C was significantly smaller (p < 0.001).The amplitude of the different phases of longitudinal motion, as well as the maximum longitudinal displacement , that is, the difference between the most antegrade and the most retrograde position of the intima‐media complex during the cardiac cycle, irrespective of phase, at baseline (rest) for both young and older subjects are given in Table 3.2p < 0.001 and p < 0.001, respectively). Further, CCA blood flow systolic velocity as well as CCA shear stress and distension increased significantly . Further, CCA strain (the relative diameter change) increased (p < 0.001), and DC decreased (p < 0.001). No significant change in CCA end‐diastolic diameter or IMT was seen. The measurements at peak exercise for both young and older subjects are summarized in Table During exercise heart rate and blood pressure increased as expected (3.2.1p < 0.001). In the subjects (n = 33) that had a distinct A at rest (baseline) the magnitude of this phase increased by mean 2565% (range −100%–68602%), although in five young subjects A seemed to decrease, or stay at approximately the same amplitude, during exercise. For comparison the distension increased by mean 44% (range 5%–91%). Typical examples of the changes in longitudinal motion during exercise in subjects having a distinct A at rest are seen in Figure n = 6), a distinct phase A became clearly apparent and increased markedly during exercise in five of them ; for examples see Figure The longitudinal motion of the intima‐media complex of the carotid artery underwent marked changes in response to physical activity, already at low load, with most evident a marked increase of the first antegrade displacement in early systole (A) . As mentioned above, in five of the young subjects A seemed to decrease or stay at approximately the same amplitude during the physical activity performed. Regarding three of these subjects, interestingly, they had by far the largest A at baseline.When young and older subjects were analyzed separately there was a significant increase of A in both young and older subjects (young p < 0.001). This was also seen when young and older subjects were analyzed separately .Also, B, the retrograde motion following A, increased significantly during exercise (The antegrade phase C showed no clear trends (and C was often somewhat hard to measure due to its indistinct termination).p < 0.001). This was also seen when young and older subjects were analyzed separately .W, the distinct retrograde motion before the onset of A, increased significantly .LMovMax increased significantly during exercise The amplitudes of the longitudinal motion at peak exercise are summarized in Table Due to the changes in amplitudes and especially the marked changes of A, the basic pattern of motion, that is, the relations between the different phases, changed in all subjects.3.2.2r = 0.47, p < 0.00001). In several individuals the correlation between systolic blood pressure and the amplitude of A was remarkable strong; for examples see Figure r‐values close to one in some individuals . However, as stated above, in a few individuals A did not increase during the experiment. When young and older subjects were analyzed separately the significant correlation between the amplitude of A and systolic blood pressure remained ; .There was a significant positive correlation between the amplitude of A and systolic blood pressure . No significant correlation between the amplitude of C and systolic pressure was seen. There was a significant positive correlation between the amplitude of W and systolic blood pressure . This correlation remained also when young and older subjects were analyzed separately . There was a weak negative correlation between the amplitude of X and systolic blood pressure .There was a significant, but weaker, positive correlation between the amplitude of B and systolic pressure . When young and older subjects were analyzed separately this correlation remained in young  but not in older subjects.There was a significant correlation between systolic pressure and LMovMax .There were significant correlations between CCA distension (diameter change) and all phases of longitudinal movement except W  intramural shear strain was estimated. Thus, the longitudinal motion of not only the intima‐media complex but also the longitudinal motion of the adventitial region was analyzed, focusing on phase A, that is, the difference in longitudinal motion between A of the intima media complex and A of the adventitial region. To measure this during exercise is an especially challenging task (see Discussion and Methods) and only the subjects with the very best quality recordings were analyzed. Further, subjects with a distinct A were chosen. Intramural shear strain increased significantly during exercise . The percentage mean increase of intramural shear strain were 177% at 90 W and 296% at peak exercise.In a subgroup of the investigated subjects (p = 0.03), but not at peak exercise (p = 0.09)  Table . The gror = 0.51, p < 0.0000001).Figure 3.2.6p < 10–5). The mean differences for LMovMax and the different phases of movement were 2 ± 94, 11 ± 61, −3 ± 64, 2 ± 81, 7 ± 43, and 2 ± 17 μm, respectively.The averaging and compensation algorithm was able to compensate for the low frequency motion due to breathing  undergoes marked changes in response to exercise already at low workload. The most prominent change is an increase (or emergence) of the antegrade displacement (A), that is, in the direction of blood flow, seen in early systole, that is, when the artery begins to distend. As expected, due to the low workload, the increase in heart rate and blood pressure in this study are moderate. Despite this, significant correlations between longitudinal displacement and blood pressure were seen, especially between the first antegrade motion A and systolic blood pressure, and in some subjects the correlation was remarkably strong. In contrast, no correlation between CCA max systolic blood flow velocity or shear stress, respectively, and the antegrade motion A was seen. We hypothesize that the increase in longitudinal displacement of the arterial wall, especially the increase in the first antegrade motion (A), is an important overlooked “cushioning” mechanism in response to increase in blood pressure and stroke volume to reduce forces/stresses within/at the wall as discussed below. Further, it seems reasonable that the changes in longitudinal motion can have impact on the circulation of the vasa vasorum, as well as on endothelial function and the smooth muscle cells and the extracellular matrix components of the media as discussed below.To study the longitudinal motion of the carotid artery wall during physical activity is a challenging task given that the vessel wall is only a few mm thin, the movements are less than a mm, and the subjects investigated are moving. To minimize these problems, we have chosen to study the response to exercise using a supine bike with a soft holder to stabilize the head, and the upper part of the body resting on the bike, thereby minimizing disturbing movements of the upper part of the body during the ultrasound registrations. In this study, we have also chosen to increase workload step wise with 20 W every second minute. One reason for this was to ensure enough time to achieve several very good quality ultrasonic recordings of the longitudinal motion at each step of workload. To be able to measure the longitudinal motion of the arterial wall, it is critical to achieve very high‐quality ultrasonic recordings of the vessel wall with distinct visualization of the intima media complex and the adventitial region during the whole cardiac cycle. The Borg Scale of perceived exertion was used to rate the intensity of the physical activity Borg, , and as Physical activity is associated with increased levels of circulating catecholamines. In healthy subjects the most obvious response to exercise is increase in heart rate, stroke volume and systolic and pulse pressure. In the present study we show that apart from a marked increase, or emergence of, an antegrade motion in early systole (A) there is also an increase in the retrograde phase B, following A, and of the retrograde phase W as well as in LMovMax.In previous experiment on the porcine carotid artery of anesthetized pigs we have shown that the longitudinal motion is profoundly influenced by adrenaline and noradrenaline, and that increase in longitudinal motion seems to be strongly related to α‐adrenoceptor activation  to flow pulsations, also known as the “Windkessel function”. Simplified, the main role of arteries as cushions is to smooth out the pressure oscillations resulting from intermittent ventricular ejection. Large elastic arteries can instantaneously accommodate the volume of blood ejected from the ventricles, storing part of the stroke volume during systole, and draining this volume during diastole, thus permitting continuous perfusion of peripheral organs and tissues. The efficiency of arteries as cushions depends on the compliance and distensibility of the arterial walls and on the viscoelastic properties of the vessels. Arterial wall viscoelasticity also affects the speed of wave propagation (pulse‐wave velocity) and the timing of wave reflections. Stiffening of the arteries increases pulse‐wave velocity and may cause an earlier return of the reflected wave (Safar 1996). Increased stiffness of large central arteries has been shown to be an independent risk factor for cardiovascular mortality  were lower in the older age group than in the young. Further, as expected blood pressures were higher in the older age‐group than in the young. Blood flow velocity in the CCA is age‐dependent  in 25% of the subjects and that the amplitude of A did increase several 100% in some individuals at the same time the distension did not increase more than 90% in any subjects. However, further studies are needed to elucidate this.It is obviously difficult to determine the forces behind the different phases of the longitudinal movement as the hemodynamic forces are so intertwined  this study cannot describe the changes at high load with high heart rate and high blood pressures. In this study we have focused on the changes during physical activity and the changes post‐exercise have not been analyzed in detail. However, after 5 min of rest the longitudinal motion had basically returned to its initial appearance.In this study we did not expect to elicit steady‐state response at each stage of load; our goal was primarily to be able to measure the longitudinal motion during some degree of physical activity and increase in blood pressure. However, in future studies it can be interesting to study the longitudinal motion also during steady state.In our previous study on aging (Cinthio et al., Shear strain is normally defined on a bulk medium, whereas the measurement of shear strain in this study is performed on vessel wall tissue, which is inhomogeneous. Since we cannot study all the arterial wall layers separately, due to the resolution of the ultrasound scanner, we have chosen to use a simplified model and thus in the calculations view the arterial wall as one medium. However, we have previously reported that the largest longitudinal displacement take place in or close to the demarcation between the media and the adventitia, that is, most likely at the external elastic lamina (Nilsson et al., In conclusion, this study shows that the multiphasic bidirectional longitudinal motion of the human carotid artery undergoes marked changes during exercise already at low workload, with most evident a marked increase/emergence of an antegrade motion in early systole. The increase seems to be linked to increase in blood pressure but not to blood flow velocity or wall shear stress. The results of this study give further support to our previous notion that the longitudinal motion of the arterial wall can be of fundamental importance for vascular hemodynamics and biology, and thus, for the study of atherosclerosis and vascular diseases.The study was approved by the Ethics Committee, Lund University, and informed consent according to the Helsinki Declaration was obtained from all subjects.This study was supported by grants from the Swedish Research Council, the Medical Faculty, Lund University, the Skåne County Council's Research and Development Foundation, and Funds at Skåne University Hospital.The authors have no conflicts of interest.


Emerging evidence among adolescents suggests that arterial stiffness temporally precedes elevated blood pressure/hypertension in the casual pathway. It remains unknown whether insulin resistance and body composition mediate this relationship. Therefore, we examined the mediating role of total fat mass, lean mass, and insulin resistance in the association between arterial stiffness and blood pressure among adolescents.We studied 3,764 participants, aged 17 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) United Kingdom birth cohort. Arterial stiffness accessed with Vicorder device measured carotid-femoral pulse wave velocity (cfPWV), body composition was measured by dual-energy Xray Absorptiometry, blood pressure by Omron device, and homeostatic model assessment of insulin resistance (HOMA-IR) was computed. Data were analysed with structural equation models mediation path analyses and adjusted for cardiometabolic and lifestyle factors.p for all = 0.002]. Lean mass  and HOMA-IR  but not total fat mass  partly mediated the association of cfPWV with systolic blood pressure after full adjustments. Similarly, lean mass  and HOMA-IR  but not total fat mass  partly mediated the association of cfPWV with diastolic blood pressure.Among 1,678 [44.6%] male and 2,086 [55.4%] female participants, higher cfPWV was directly and independently associated with higher systolic and diastolic blood pressure, irrespective of the mediator [Standardized regression coefficient (β) = 0.248–0.370, Attenuating insulin resistance may be a potentially valuable strategy in lowering higher blood pressure precipitated by higher arterial stiffness. The prevalence of elevated blood pressure and hypertension in youth remains high despite interventions targeted at decreasing the global burden –4. It haThe prevention of elevated blood pressure and hypertension requires further understanding of the mechanistic path through which causative factors such as arterial stiffness exert their influence , 4, 6–9.via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time  measurements at the age 17-year clinic visit. The demographic characteristics of excluded participants were similar to those included in this study as reported earlier (the time –13. ConsAnthropometry (height and weight) at 17 years of age was assessed using a stadiometer  and body mass (kilogram) using electronic weighing scales   portable physiologic vascular testing equipment. All measurements were taken independently by one of two trained vascular technicians   medical history such as a history of hypertension, diabetes, high cholesterol, and vascular disease. Moderate to vigorous physical activity at ages 15.5 years was assessed with ActiGraphTM accelerometer worn for 7 days. Moderate to vigorous physical activity cut point was > 2,296 counts per minute ; the association of total fat mass, lean mass, or HOMA-IR with systolic and diastolic blood pressure (Equation 2); and the association of cfPWV with systolic and diastolic blood pressure (Equation 3), and Equation 3’ accounted for the mediating role of fat mass, lean mass or HOMA-IR. The proportion of mediating roles was estimated as the ratio of the difference between Equation 3 and Equation 3’ or the multiplication of Equations 1 and 2 divided by Equation 3 and expressed in percentage. A mediating or indirect role is confirmed when there are statistically significant associations between (a) the predictor and mediator, (b) the predictor and outcome, (c) the mediator and outcome, and when (d) the association between the predictor and outcome variable was attenuated upon inclusion of the mediator , 17. Patp-value < 0.05 as statistically significant and made conclusions based on standardized regression coefficients and p-value. Missing data were accounted for using regression imputations within the structural equation model prior to mediation analysis. Studies involving four thousand ALSPAC children with 0.8 statistical power, 0.05 alpha, and 2-sided p-value would show a minimum detectable effect size of 0.049 standard deviations if they had relevant exposure to a normally distributed quantitative variable .The datasets presented in this article are not readily available because the informed consent obtained from ALSPAC participants does not allow the data to be made freely available through any third-party maintained public repository. However, data used for this submission can be made available on request to the ALSPAC Executive. The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. Full instructions for applying for data access can be found here: The studies involving human participants were reviewed and approved by Avon Longitudinal Study of Parents and Children Ethics and Law Committee and the Local Research Ethics Committees, University of Bristol, United Kingdom. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.AA had full access to all the data in the study, took responsibility for the integrity of the data and the accuracy of the data analysis, did concept and design, acquisition, analysis, or interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, obtained funding, and approved the submitted version.