Angiotensin Receptor Antagonists Research Articles

Tolerability of Antihypertensive Medications: The Influence of Age.

Despite high prevalence of hypertension, few studies have analysed the adverse effects (AEs) of antihypertensive medications, especially in older patients. To investigate the prevalence and associated factors of antihypertensive-related AEs, focusing on the influence of age on treatment tolerability. We retrospectively investigated antihypertensive-related AEs in patients evaluated at the Hypertension Clinic of Careggi Hospital, Florence, Italy, between January 2017 and July 2020. Multivariable regression models were generated to analyse variables associated with AEs in the overall sample and in participants ≥75 years. Among 622 subjects (mean age 64.8 years, 51.4% female), the most frequently reported AEs were calcium-channel blockers (CCB)-related ankle swelling (26.8%) and ACEi-induced cough (15.1%). Ankle swelling was more common in older patients (35.7% vs 22.3%, p = 0.001; odds ratio [OR] 1.94, 95%CI 1.289-2.912) and was independently associated with Body Mass Index (BMI, adjOR 1.073) and angiotensin-receptor antagonists (adjOR 1.864). The association with BMI was confirmed in older patients (adjOR 1.134). ACEi-induced cough showed similar prevalence in younger and older patients (13.9% vs 15.6%, p = 0.634), being independently associated with female sex (adjOR 2.118), gastroesophageal reflux disease (GERD, adjOR 2.488) and SNRI therapy (adjOR 8.114). The association with GERD was confirmed in older patients (adjOR 3.238). CCB-related ankle swelling and ACEi-induced cough represent the most common antihypertensive-related AEs, also at old age. Older patients showed a two-fold increased risk of ankle swelling, that was also independently associated with BMI. ACEi-induced cough had similar prevalence at younger and old ages, being independently associated with GERD.

Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety

Rationale and ObjectiveSparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist (DEARA) examined in the ongoing phase 2 DUET trial for focal segmental glomerulosclerosis (FSGS). In the DUET 8-week double-blind period, sparsentan resulted in greater proteinuria reduction versus irbesartan. We report the long-term efficacy and safety of sparsentan during the open-label extension over more than 4 years. Study DesignPatients were examined from their first sparsentan dose (double-blind period or open-label extension) through 4.6 years. Setting and ParticipantsPatients with FSGS, excluding secondary FSGS. InterventionSparsentan (200, 400, and 800mg/day). OutcomesUrine protein/creatinine ratio (UP/C), FSGS partial remission endpoint (UP/C≤1.5g/g and >40% reduction from baseline), eGFR, and blood pressure approximately every 12 weeks. Treatment-emergent adverse events by year and cases/100 patient-years. Results109 patients were enrolled; 108 received ≥1 sparsentan dose; 103 entered the open-label extension (68 sparsentan, 35 irbesartan during double-blind period). Sparsentan was ongoing in 45/108 patients (41.7%); median time to treatment discontinuation was 3.9 years (95%CI, 2.6-5.2). Mean percent proteinuria reduction from baseline was sustained through follow-up. Achieving partial remission within 9 months of first sparsentan dose (52.8% of patients) versus not achieving (47.2%) was associated with significantly slower rate of eGFR decline over the entire treatment period (-2.70 vs -6.56, P=0.03) and in the first 2 years (-1.69 vs -6.46, P=0.03). The most common treatment-emergent adverse events (>9 cases/100 patient-years) were headache, peripheral edema, upper respiratory infection, hyperkalemia, and hypotension. Peripheral edema and hypotension declined from year 1 (13.9% and 15.7% of patients, respectively) to ≤4% in years ≥2. There were no cases of heart failure and no patient deaths. LimitationsThe open-label extension does not include a comparison group. ConclusionsLong-term sparsentan treatment showed sustained proteinuria reduction and a consistent safety profile.

The protective effects of Irbesartan in cognitive impairment in hypertension.

Vascular cognitive impairment (VCI) is claimed as the second most common type of dementia after Alzheimer's disease (AD), in which hypertension is a critical inducer. Currently, hypertension-induced cognitive impairment lacks clinical treatments. Irbesartan is a long-acting angiotensin receptor antagonist with promising antihypertensive properties. Our research will focus on the potential function of Irbesartan on hypertension-induced cognitive impairment. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were orally dosed with normal saline or 20 mg/kg/day Irbesartan for 14 consecutive days, with 4 groups divided shown as below: WKY, Irbesartan, SHR, SHR+ Irbesartan. Firstly, the markedly increased systolic blood pressure observed in SHR rats was signally repressed by Irbesartan on Day 7 and 14 post-dosing. Moreover, notably decreased time of exploring the novel object in the object recognition task (ORT) test, elevated escape latency, and reduced time in the target quadrant in the Morris water maze (MWM) test were observed in SHR rats, which were prominently reversed by Irbesartan. Furthermore, the declined superoxide dismutase (SOD) activity, elevated malondialdehyde (MDA) level, increased cyclin-dependent kinase-5 (CDK5) activity, and enhanced protein level of p35/p25, p-Tau (pSer214)/Tau46, and brain-derived neurotrophic factor (BDNF) were memorably rescued by Irbesartan. Lastly, the activity of cAMP/cAMP response element binding protein (CREB) signaling in the hippocampus of SHR rats was markedly repressed, accompanied by an upregulation of phosphodiesterase 4B (PDE4B), which was observably rescued by Irbesartan. Collectively, Irbesartan protected against the hypertension-induced cognitive impairment in SHR rats by regulating the cAMP/CREB signaling.

Sparsentan ameliorates glomerular hypercellularity and inflammatory-gene networks induced by IgA1-IgG immune complexes in a mouse model of IgA nephropathy.

IgA nephropathy (IgAN) is characterized by glomerular deposition of immune complexes (ICs) consisting of IgA1 with O-glycans deficient in galactose (Gd-IgA1) and Gd-IgA1-specific IgG autoantibodies. These ICs induce kidney injury, and in the absence of disease-specific therapy, up to 40% of patients with IgAN progress to kidney failure. IgA1 with its clustered O-glycans is unique to humans, which hampered development of small-animal models of IgAN. Here, we used a model wherein engineered ICs (EICs) formed from human Gd-IgA1 and recombinant human IgG autoantibody are injected into nude mice to induce glomerular injury mimicking human IgAN. In this model, we assessed the protective effects of sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) versus vehicle on EIC-induced glomerular proliferation and dysregulation of gene expression in the kidney. Oral administration of sparsentan (60 or 120 mg/kg daily) to mice intravenously injected with EIC attenuated the EIC-induced glomerular hypercellularity. Furthermore, analysis of changes in the whole kidney transcriptome revealed that key inflammatory and proliferative biological genes and pathways that are upregulated in this EIC model of IgAN were markedly reduced by sparsentan, including complement genes, integrin components, members of the mitogen-activated protein kinase family, and Fc receptor elements. Partial overlap between mouse and human differentially expressed genes in IgAN further supported the translational aspect of the immune and inflammatory components from our transcriptional findings. In conclusion, our data indicate that in the mouse model of IgAN, sparsentan targets immune and inflammatory processes leading to protection from mesangial hypercellularity.NEW & NOTEWORTHY The mechanisms by which deposited IgA1 immune complexes cause kidney injury during early phases of IgA nephropathy are poorly understood. We used an animal model we recently developed that involves IgA1-IgG immune complex injections and determined pathways related to the induced mesangioproliferative changes. Treatment with sparsentan, a dual inhibitor of endothelin type A and angiotensin II type 1 receptors, ameliorated the induced mesangioproliferative changes and the associated alterations in the expression of inflammatory genes and networks.

Sparsentan is superior to losartan in the gddY mouse model of IgA nephropathy.

The mechanism leading to the development of IgA nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation, and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist (DEARA), recently received accelerated approval in United States for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. Four-week-old gddY mice were given control chow, chow containing sparsentan, or drinking water containing losartan until 12 or 20 weeks old. Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, ETAR, and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared to AT1R antagonism alone.

Practical Considerations for the Use of Sparsentan in the Treatment of Patients with IgAN in Clinical Practice.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is characterized by the mesangial deposition of IgA-containing immune complexes, triggering damage to the glomerular filtration barrier that is amplified by the tandem action of endothelin-1 and angiotensin II at their receptors. Proteinuria and progressive glomerular damage cause loss of kidney function in up to 50% of patients within 10-20 years. The risk of progression is strongly associated with persistent proteinuria (>0.75-1 g/day). Current standard of care involves interventions to decrease proteinuria and control blood pressure. Immunosuppressive agents, used in selected patients at high risk for progression, can be associated with significant side effects. Sparsentan, a novel non-immunosuppressive single-molecule Dual Endothelin Angiotensin Receptor Antagonist (DEARA), received FDA accelerated approval based on interim results from the PROTECT trial, which demonstrated that sparsentan-treated patients achieved a significantly greater reduction in proteinuria from baseline versus the active control irbesartan and that sparsentan was generally safe and well tolerated. Sparsentan is the first non-immunosuppressive treatment to be FDA-approved for the reduction of proteinuria in adults with IgAN at high risk of disease progression. We provide practical guidance for the clinical use of sparsentan in adults with IgAN.

Lactobacillus induced by irbesartan on spontaneously hypertensive rat contribute to its antihypertensive effect.

Hypertension is linked to gut dysbiosis. Here, the impact of the angiotensin receptor antagonist irbesartan on the gut microbiota of spontaneously hypertensive rats (SHR) were investigated. In addition, we assessed their contribution to its antihypertensive effect. Eight-week-old Wistar-Kyoto (WKY) rats and SHR were administered irbesartan for 8 weeks. Fecal microbiota transplantation (FMT) was performed from SHR treated with irbesartan or untreated SHR to recipient untreated SHR. The preventive effect of Lactobacillus on hypertension in SHR was evaluated. Blood pressure (BP) was calculated using a tail-sleeve sphygmomanometer. To better assess the composition of the gut microbiota, the V3-V4 region of the 16S rRNA gene was amplified while short-chain fatty acids (SCFAs) in feces were tested by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Irbesartan restored gut dysbiosis, increased the abundance of Lactobacillus , and improved anti-inflammatory ability, antioxidative ability, intestinal integrity, and intestinal inflammation in SHR. The microbiota in SHR-treated irbesartan could reduce BP and improve antioxidative ability and gut integrity in SHR. Lactobacillus johnsonii ( L. johnsonii ) and Lactobacillus reuteri ( L. reuteri ) reduced BP, restored gut dysbiosis and improved anti-inflammatory ability, antioxidative ability, intestinal integrity in SHR. Most notably, irbesartan, L. johnsonii , and L. reuteri can significantly increase SCFA content in SHR feces. The current study demonstrated that irbesartan treatment ameliorated gut dysbiosis in SHR. Irbesartan induced alterations in gut microbiota, with increased prevalence of Lactobacillus .

Effect of semaglutide on global longitudinal strain and global myocardial work efficiency in patients with uncontrolled type 2 diabetes mellitus and obesity

Abstract Background Type 2 Diabetes mellitus (T2DM) increases of two-to three-fold the risk of cardiovascular disease (CVD). Cardiovascular outcome trials (CVOTs) demonstrated that glucagon-like peptide 1-receptor agonists (GLP1-RAs), as semaglutide in SUSTAIN-6 study, have effectively reduced CV risk in T2DM patients, so their use is recommended by guidelines. Purpose The objective of our work was to evaluate the effect of Semaglutide administration in a cohort of uncontrolled diabetic patients (within 5 years from diagnosis) on oxidative stress validated markers (8-isoprostane and NOX-2), platelet activation indicators (Sp-Selectin) and subclinical myocardial damage evaluated by measurement of deformation and efficiency parameters, obtained by speckle tracking echocardiography (STE). Methods We enrolled 70 Caucasian patients (mean age 65.5±8.2) with T2DM and obesity, 54 men and 16 women, 85.7% with hypertension, 14.2% with chronic obstructive pulmonary disease, 57.1% with sleep apnea syndrome, 18.5% with chronic kidney disease, and 41.4% with dyslipidemia. All patients were treated with statins and metformin, 42.8% with insulin, 24.2% with diuretics, 37.1% with ACE inhibitors, and 48.5% with angiotensin receptor antagonists. In the study the mean dose of semaglutide was 0.59±0.29 mg/week, no serious adverse events were reported. Results After 6 months of follow-up a significant improvement in fasting plasma glucose, insulinemia, HOMA, IGF-1, HbA1c and BMI (p<0.0001) was reported. In addition, there was a significant reduction in biomarkers of oxidative stress such as 8-isoprostane, Nox-2 and uric acid (p<0.0001), biomarkers of platelet activity such as Sp-Selectin and high-sensitivity C-reactive protein (hs-CRP) (p<0.0001). Moreover, we observed a significant improvement in left ventricular myocardial deformation parameters such as Global longitudinal strain (GLS) (p<0.0001) and global myocardial work efficiency (GWE) (p<0.0001). The linear correlation analysis showed that variation (Δ) GLS was inversely correlated with ΔHOMA (p=0.011), Δuric acid (p=0.025) and ΔSp-selectin (p<0.0001); ΔGWE was inversely correlated with ΔHOMA (p=0.011), Δuric acid (p=0.025) and ΔSp-selectin (p<0.0001). From stepwise multivariate linear regression model, ΔSp-selectin, ΔHOMA and Δuric acid justifying 27.8%(p<0.0001), 5.6%(p=0.010) and 4.4%(p=0.023) of ΔGLS variation, respectively. Instead ΔNOX-2, Δhs-CRP and ΔBMI justifying 22.3%(p<0.0001), 15.6%(p<0.0001), and 4.0%(p=0.022) of ΔGWE variation, respectively. Conclusion Treatment for 6 months with Semaglutide, in patients with uncontrolled T2DM and obesity, improved GLS and GWE. It’s plausible that this improvement may be justified by the reduction of inflammatory, oxidative stress and platelet activation parameters together with favorable metabolic changes; thus promoting coronary microcirculation protection with positive effects on myocardial contractility.

Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis

BackgroundAn unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin–angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown.MethodsIn this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated.ResultsA total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P=0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], −1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, −1.3 to 3.0). The mean change in eGFR from baseline to week 112 was −10.4 ml per minute per 1.73 m2 with sparsentan and −12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, −1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups.ConclusionsAmong patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.)

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. Travere Therapeutics.

Meta-analysis of the effect of losartan relative to other angiotensin receptor antagonists on serum uric acid level

Purpose: To systematically analyze the disparity in uric acid reduction between losartan and other angiotensin receptor antagonists.Methods: A computer-based search was conducted in databases including EMBASE, PubMed, Wanfang, CNKI, Ovid MEDLINE, and Web of Science to identify original literature comparing the impact of losartan with other angiotensin receptor antagonists on blood uric acid levels. Utilizing the Cochrane Collaboration bias risk tool, a quality assessment of the included randomized controlled studies was conducted.Results: A total of 12 publications were obtained, consisting of 6 randomized controlled studies and 6 cohort studies. Five of the twelve publications assessed the impact of losartan compared to valsartan on blood uric acid levels. The heterogeneity analysis yielded I2 = 98 % (p < 0.01), indicating substantial variability among the studies. Findings indicated that losartan was more effective than valsartan in reducing blood uric acid levels (SMD = -3.26, 95 % CI (-5.01 to 1.51), p < 0.05). Four publications investigated the impact of losartan versus telmisartan on blood uric acid levels. The results revealed that losartan had a greater effect in reducing blood uric acid levels compared to telmisartan (SMD = -1.77, 95 % CI (-3.411 to -0.13), p < 0.05).Conclusion: Among the angiotensin receptor antagonists used as antihypertensive drugs, losartan stands out for its significant ability to reduce uric acid levels. This finding provides a strong evidencebase for making clinical medication decisions.

Risk factors for hypokalemia and its association with postoperative recovery in patients scheduled for radical gastrectomy: a retrospective study

BackgroundHypokalemia is common in patients of various operations, especially gastrointestinal surgery, which seriously affects the safety and enhanced recovery after surgery. Our study aims to explore the risk factors of preoperative hypokalemia of radical gastrectomy for gastric cancer and analyze its impact on postoperative recovery.MethodsA total of 122 patients scheduled for radical gastrectomy from September, 2022 to December, 2022 were retrospectively analyzed. According to the serum potassium level before skin incision, patients were divided into hypokalemia group (n = 64) and normokalemia group (n = 58). Factors including age, gender, BMI, ASA classification, glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), creatinine, blood urea nitrogen (BUN), albumin, hypertension history, whether taking calcium channel blockers, β-receptor blockers, angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor antagonist (ARB), thiazide diuretics and other drugs, anemia history, diabetes mellitus history, inability to eat or intestinal obstruction, vomiting, diarrhea, hypokalemia on admission and whether under cooperation with clinical nurse specialist were compared between groups. Univariate logistic regression analysis was used to determine risk factors for hypokalemia with p < 0.2 included as a cutoff. Multivariate logistic regression was used to analyze the influencing factors of preoperative hypokalemia for the indicators with differences. A receiver operating characteristic (ROC) curve was used to evaluate the efficacy of the regression model. Primary exhaust time and defecation time after surgery were compared between the two groups.ResultsThe use of ACEI or ARB [OR 0.08, 95% CI (0.01 to 0.58), p = 0.012] and thiazide diuretics [OR 8.31, 95% CI (1.31 to 52.68), p = 0.025], inability to eat for more than 3 days or intestinal obstruction [OR 17.96, 95% CI (2.16 to 149.43), p = 0.008], diarrhea for more than 48 h [OR 6.21, 95% CI (1.18 to 32.61), p = 0.031] and hypokalemia on admission [OR 8.97, 95% CI (1.05 to 77.04), p = 0.046] were independent influencing factors of hypokalemia before skin incision. Primary postoperative exhaust time and defecation time was significantly longer in the hypokalemia group than in the normokalemia group, no matter after laparoscopic radical gastrectomy (p = 0.044, p = 0.045, respectively) or open radical gastrectomy (p = 0.033, p = 0.019, respectively).ConclusionEarly attention and management of serum potassium in patients undergoing radical gastrectomy can better reduce perioperative adverse reactions and promote recovery of gastrointestinal function.

Novel Diabetic Nephropathy-Based Hypertension Treatment for Type-2 Diabetes Mellitus and CKD Patients: A Mini Review

Diabetes mellitus is known to result in persistent renal impairment among individuals with the condition and is presently the primary aetiology of terminal-stage renal disease, with more than fifty percent of dialysis patients being affected. The prevalence of diabetes continues to rise, resulting in a decline in individuals' health status and imposing significant financial burdens on healthcare systems. Accurately distinguishing between the various types of diabetes is crucial in order to provide appropriate treatment that mitigates the severity of associated complications and their significant consequences. The co-occurrence of diabetes and renal disease has been found to be linked with a significant fourfold rise in both the frequency and fatality of cardiovascular disease. Pharmacological interventions aimed at reducing blood pressure have been a crucial component in the management of diabetic nephropathy for several decades. The past decade has witnessed a decline in the occurrence of end-stage renal disease, owing to enhanced care measures such as the administration of hypertension medication. It is assumed in clinical practice recommendations that angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists hold an equivalent status. The efficacy of low doses of ACEI and ARB in reducing proteinuria was found to be superior to that of high doses. The co-administration of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) has been observed to elicit a more pronounced reduction in 24-hour proteinuria and urinary albumin excretion rate (UAER) in comparison to the singular administration of either ACEI or ARB.

Proteinuria as a Surrogate Endpoint for Disease Progression in IgA Nephropathy: Predicting Long-Term Treatment Effects of Sparsentan

IgA nephropathy (IgAN) is a rare, life-limiting disease for which there is significant unmet need. Until recently, drug development for IgAN had been impeded by the requirement for large-scale, long-term clinical trials to measure clinical outcomes. However, the recent establishment of ‘reduction in proteinuria’ as a surrogate endpoint to predict clinical outcomes in IgAN, as a basis for accelerated drug approval, has transformed the field. At the 60th European Renal Association (ERA) Congress in June 2023, two oral poster presentations focused on the use of early reduction in proteinuria as an endpoint for clinical studies in IgAN. Alex Mercer, Consultant in Clinical Drug Development at JAMCO Pharma Consulting in Stockholm, Sweden, presented data estimating the long-term clinical outcome of reductions in proteinuria (clinically meaningful extensions in time to kidney failure or death), which could help predict the future protective effect of any new intervention on kidney function. Following this, Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, and Honorary Consultant Nephrologist at Leicester General Hospital, UK, described findings from the prespecified interim analysis of the Phase III PROTECT study of sparsentan (a novel dual endothelin angiotensin receptor antagonist) in IgAN, which included reduction in proteinuria as a primary endpoint. In patients with IgAN at high risk of disease progression, sparsentan produced a rapid and significant reduction in proteinuria of a level that, according to the study data presented by Mercer, would correspond to a substantially lowered risk of kidney failure or death. Long-term data to confirm this predicted clinical outcome on disease progression are anticipated.

Sacubitril/valsartan and arrhythmic burden in patients with heart failure and reduced ejection fraction: a systematic review and meta-analysis.

The aim of this study was to assess whether angiotensin receptor/neprilysin inhibitor (ARNI) decreases ventricular arrhythmic burden compared to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonist (ACE-I/ARB) treatment in chronic heart failure with reduced ejection fraction (HFrEF) patients. Further, we assessed if ARNI influenced the percentage of biventricular pacing. A systematic review of studies (both RCTs and observational studies) including HFrEF patients and those receiving ARNI after ACE-I/ARB treatment was conducted using Medline and Embase up to February 2023. Initial search found 617 articles. After duplicate removal and text check, 1 RCT and 3 non-RCTs with a total of 8837 patients were included in the final analysis. ARNI was associated with a significative reduction of ventricular arrhythmias both in RCT (RR 0.78 (95% CI 0.63-0.96); p = 0.02) and observational studies (RR 0.62; 95% CI 0.53-0.72; p < 0.001). Furthermore, in non-RCTs, ARNI also reduced sustained (RR 0.36 (95% CI 0.2-0.63); p < 0.001), non-sustained VT (RR 0.67 (95% CI 0.57-0.80; p = 0.007), ICD shock (RR 0.24 (95% CI 0.12-0.48; p < 0.001), and increased biventricular pacing (2.96% (95% CI 2.25-3.67), p < 0.001). In patients with chronic HFrEF, switching from ACE-I/ARB to ARNI treatment was associated with a consistent reduction of ventricular arrhythmic burden. This association could be related to a direct pharmacological effect of ARNI on cardiac remodeling.Trial registration: CRD42021257977.

RETRACTED ARTICLE: Effects of Dapagliflozin on myocardial remodeling, inflammatory factors, and cardiac events in heart failure with preserved ejection fraction.

To investigate the effects of Dapagliflozin on myocardial remodeling, inflammatory factors, and cardiac events in the treatment of heart failure with preserved ejection fraction (HFpEF). Ninety-two patients with HFpEF treated in our hospital from August 2021 to March 2022 were retrospectively picked as study subjects. These subjects were randomized as the study group and control group following the random number table, with 46 cases in each group. Patients in the control group adopted standard anti-heart failure (HF) treatment, including diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists β receptor blockers, and digitalis. Patients in the study group received Dapagliflozin on the basis of the control group. Changes in myocardial remodeling-related parameters [left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), the ratio of early diastolic blood flow velocity to late diastolic blood flow velocity (E/A), plasma N-terminal B-type brain natriuretic peptide precursor (NT-proBNP), and cardiac troponin I (CTnI)] were assessed by echocardiography before and 12months after the intervention. The content of inflammatory factors [interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)] in serum was measured by enzyme-linked immunosorbent assay. The factors affecting the clinical efficacy of Dapagliflozin were analyzed by the multivariate logistic regression. The incidence of cardiac events was compared between the two groups. The effective rate of 95.65% in the study group was much higher than 80.43% in the control group (P < 0.05). After the intervention, the study group had an especially higher content of LVEF and E/A and sharply lower content of LVEDD, NT-proBNP, and CTnI than the control group (P < 0.001). After the intervention, IL-1β, TNF-α, and IL-6 levels were markedly lower in the study group than in the control group (P < 0.001). The incidence of cardiac events, including arrhythmias, recurrent angina, heart failure rehospitalization, cardiogenic death, and all-cause mortality, was 8.70% in the study group and 26.09% in the control group, which was much lower in the study group (P < 0.05). The results of multivariate logistic regression analysis showed that LVEF and E/A were independent protective factors affecting the ineffectiveness of Dapagliflozin (P < 0.05), and LVEDD, NT-proBNP, CTnI, IL-1β, TNF-α, and IL-6 were independent risk factors affecting the ineffectiveness of Dapagliflozin (P < 0.05). In conclusion, Dapagliflozin could effectively improve myocardial remodeling, inhibit inflammatory reaction, and play a more active role in the treatment of patients with HFpEF, providing a certain clinical basis for the treatment of patients.

Irbesartan has a curative effect on lipopolysaccharide-induced cardiotoxicity by antioxidant and antiapoptotic pathways

Introduction and ObjectiveLipopolysaccharide (LPS) has been associated with myocardial inflammation, oxidative stress, apoptosis, and cardiac dysfunction, as well as death by causing sepsis. In this study, we investigated the effect of irbesartan (IRB), an angiotensin receptor antagonist, on cardiotoxicity caused by LPS. MethodsThe experiment involved 24 Wistar albino rats divided into three groups of eight: control, LPS (5 mg/kg), and LPS (5 mg/kg)+IRB (3 mg/kg). Parameters including total oxidative status, total antioxidant status, oxidative stress index, and ischemia-modified albumin were measured to assess oxidative stress in heart tissues and serum. Serum CK, CK-MB, and LDH levels were measured spectrophotometrically. RT-qPCR was used to detect the mRNA expression levels of Bcl-2, BAX, p53, caspase-3, and sirtuin 1. Tissues taken from the heart and aorta were examined by immunohistochemistry and histopathology. ResultsWhile there was an increase in the parameters indicating heart damage, oxidative stress, and apoptosis in the group given LPS, there was an improvement in all parameters and heart damage in the group treated with IRB. ConclusionAs a result of our study, we determined that IRB has an ameliorating effect on myocardial damage caused by oxidative stress and apoptosis developed by the LPS-induced sepsis model.

#4057 SUPERIOR PROTEINURIA REDUCTION WITH SPARSENTAN IN IMMUNOGLOBULIN A NEPHROPATHY (IGAN): A PROTECT STUDY INTERIM ANALYSIS

Abstract Background and Aims IgAN is the most common glomerular disease worldwide. Despite optimized standard of care, most patients with IgAN progress to kidney failure within 10-15 years, consequently seriously affecting their quality of life and mortality. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed for IgAN. Sparsentan is a novel, oral, non-immunosuppressive, single molecule that is a dual endothelin and angiotensin receptor antagonist being investigated for IgAN and focal segmental glomerulosclerosis. The Phase 3 PROTECT study is examining the long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan, in adults with IgAN. Reported here are the PROTECT pre-specified interim primary efficacy endpoint and safety outcomes. Method PROTECT is an ongoing, global, Phase 3, multicenter, randomized, double-blind, active controlled study designed to evaluate the efficacy and safety of sparsentan versus the active control irbesartan in adults with IgAN with overt proteinuria despite receiving maximized treatment with an angiotensin converting enzyme inhibitor (ACEi) and/or ARB. The study duration is 270 weeks; the double-blind period is 114 weeks (110 treatment and 4 follow-up) with an open-label extension period up to 156 weeks. Adult patients with biopsy-proven IgAN (excluding IgAN secondary to another condition or IgA vasculitis), urine protein excretion value ≥1.0 g/day, eGFR ≥30 mL/min/1.73m2, systolic/diastolic blood pressure ≤150/≤100 mmHg, and on a stable dose of ACEi and/or ARB therapy for at least 12 weeks prior to screening that is both the patient's maximum tolerated dose and at least one-half of the maximum labeled dose were eligible for inclusion. Patients took their last ACEi and/or ARB dose the day before randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 400 and 300 mg/day, respectively), stratified by screening eGFR and urine protein excretion values. The pre-specified interim primary efficacy endpoint of change from baseline in urine protein/creatinine ratio (UP/C, based on a 24-hour urine sample) at Week 36 was analyzed using a mixed model repeated measures analysis. The safety evaluation included assessment of treatment emergent adverse events. Results A total of 671 patients were screened; 406 patients from clinical sites in 18 countries, including sites in North America, Europe, and Asia Pacific, met eligibility criteria and were enrolled and randomized into PROTECT. Two randomized patients withdrew from the study prior to initiating study treatment. The 404 randomized patients who received study drug were included in the primary analysis population. The mean reduction in UP/C from baseline at 36 weeks was significantly greater in the patients who received sparsentan (-49.8%) versus irbesartan (-15.1%, P&amp;lt;0.0001). Proteinuria reduction consistency across baseline demographic and clinical characteristics and rates of complete and partial remission are reported, as well as sustained proteinuria reduction over time. Safety outcomes related to edema and liver function tests are reported. Overall, sparsentan was generally well-tolerated and comparable to irbesartan. Conclusion The interim results of the PROTECT study show that in adult patients with IgAN and persistent proteinuria above 1 g/day despite being treated with ACEis and/or ARBs, once-daily treatment with sparsentan compared head-to-head with maximum labelled or tolerated irbesartan produced a robust and clinically meaningful reduction in proteinuria. The safety of sparsentan was consistent with previous studies in FSGS and comparable to irbesartan.

ANTIHYPERTENSIVE THERAPY INTAKE IN THE PURE COLOMBIA COHORT 2005-2021

Objective: Describe changes in antihypertensive therapy in prevalent hypertension (HT) cases in the PURE cohort (The Prospective Urban Rural Epidemiology) Colombia in 2005-2021. Design and method: A prospective cohort study including 7552 participants from the baseline PURE Colombia cohort from 11 departments (Atlántico, Bolívar, Caldas, Casanare, Cauca, Cesar, Cundinamarca, Nariño, Quindío, Santander, Tolima). We conducted a descriptive analysis of the change in antihypertensive therapy between the 2005 baseline and the cut-off point to 2021. Results: At baseline, 2846 (37.7%) hypertensive participants were identified, 65.7% of which were women, with a mean age of 55.2 (SD 9.2) years. After 13 years of follow-up, 902 incident cases of HT were reported, 67.2% of which were women, increasing the prevalence within the cohort to 50.2% Regarding the prevalences of antihypertensive drug use, in 2005 vs 2021 the observed changes were: angiotensin-converting enzyme inhibitors (ACEI) 23.7% vs 9.2%, thiazide diuretics (TD) 10.1% vs 6.0%, angiotensin receptor antagonists (ARBs) 4.5% vs 28.8% and lastly, dihydropyridine calcium channel blockers (DCCB) 4.0% vs 5.2%. The differences in the use of antihypertensive drugs between baseline and follow-up were significant, 55.7% of the patients reported no use of antihypertensive drugs at baseline vs 59.8% at follow-up, 20.0% were on monotherapy and the proportion dropped to 18.9%, 24.3% reported use of 2 or more drugs at baseline and 21.3% at follow-up. Conclusions: The significant increase in hypertension suggests the need to adopt recommendations for drug consumption that have abandoned the use of monotherapy; however, the changes in the management of hypertensive patients in the cohort show no improvement. There is a need to undertake strategies that encourage access to fixed-dose combination antihypertensive therapy.

Protocolo terapéutico de la hipertensión esencial

Hypertension (HT) is the main risk factor for disease and death in the world, and properly controlling it reduces the risk of associated morbimortality. Essential HT is the most common form of HT (90%-95%), and genetic as well as environmental factors are implicated in its development. When considering a therapeutic protocol in a hypertensive patient it is important to quantify the vascular risk and define a control target. Following the 2018 recommendations of the European Society of Hypertension and the European Society of Cardiology, in the majority of cases it is indicated to simultaneously commence with lifestyle modifications and pharmacological treatment. The recommendation is to always start treatment with a combined therapy, except in patients with BP close to the target and in patients who are frail or over the age of 80 years. For the majority of patients a combination of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist II (ARA II) with a calcium antagonist or a thiazide will be preferable, although we should always individualize the treatment and control targets according to the patient's profile, while also considering special situations such as heart failure, auricular fibrillation, heart disease, chronic kidney disease or resistant HT.