Association of RAAS inhibitors on osteoporosis and fracture risk in the hypertensive population-A prospective population-based cohort study in Lanzhou, China.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) inhibitors appear to benefit bone tissue in antihypertensive treatment. However, the association between RAAS inhibitors and bone metabolism was inconsistent. METHODS AND STUDY DESIGN: Based on the study of Risk Evaluation of Cancers in Chinese Diabetic Individuals(REACTION) conducted in 2011, We followed 6,252 Lanzhou residents aged 40-75 years from 2014 to 2016. Finally, 1,625 hypertension cases with complete data were included in the analysis. The study subjects were divided into four groups according to the type of antihypertensive drugs. We employed logistic or multivariate Cox proportional hazards regression to estimate the association between different antihypertensive drug use and osteoporosis, the risk of fracture, and the change in bone mineral density (BMD) level. The association of osteoporosis or the fracture risk by cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated. RESULTS: The cross-sectional study showed that there was no significant association between baseline antihypertensive drugs (angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB)) use and osteoporosis and fracture. During a mean follow-up of 3.4 years in the longitudinal study, there were 478 new osteoporosis cases and 76 fractures. Compared with patients without antihypertensive drug use, the hazard ratios (HRs) [95% confidence interval (CI)] for the risk of osteoporosis were 1.005(0.651,1.552) and 1.077(0.793,1.462) in ACEI or ARB use (p > 0.05). ACEI or ARB use was also not significantly associated with fracture risk (HR 1.102(0.326,3.726), 0.735(0.251,2.148), p > 0.05). Further analysis showed that the use of ACEI (HR 1.078(0.146,7.950)) or ARB (HR 1.169(0.347,3.939)) was not significantly associated with the improvement of osteoporosis (p > 0.05). In addition, the duration of RAAS inhibitors used showed no apparent correlation with the risk of osteoporosis (≤ 3 years: HR 0.872 (0.516, 1.474), > 3 years: HR 1.151 (0.574, 2.308)), nor with the improvement of osteoporosis and the risk of fracture. Meanwhile, the association mentioned above did not change compared to different RAAS inhibitors. CONCLUSIONS: The use of RAAS inhibitors, including ACEIs and ARBs, was not significantly associated with osteoporosis, risk of fracture, or BMD change.

Angiotensin II-Real-Life Use and Literature Review.

Angiotensin II is a recently introduced vasopressor, which has been available since 2017. The novelty and the relatively high cost of angiotensin II currently limit its broader application. It induces vasoconstriction by activating the renin-angiotensin-aldosterone system and is currently the sole vasopressor functioning through this pathway. Beyond vasoconstriction, angiotensin II also affects various other physiological processes. Current evidence supports its use in managing vasoplegic and cardiogenic shock in patients who are unresponsive to catecholamines and vasopressin. However, due to limited data, the optimal timing for initiating therapy with angiotensin II, strategies for combining it with other vasopressors, and strategies for its discontinuation remain unclear. Ongoing and planned studies aim to address some of these uncertainties. This article reviews the physiological and pathophysiological effects of angiotensin II, describes its pharmacology, and provides a narrative review of the current literature.

ACE2 alleviates sepsis-induced cardiomyopathy through inhibiting M1 macrophage via NF-κB/STAT1 signals.

Angiotensin-converting enzyme 2 (ACE2), a crucial element of the renin-angiotensin system (RAS), metabolizes angiotensin II into Ang (1-7), which then combines with the Mas receptor (MasR) to fulfill its protective role in various diseases. Nevertheless, the involvement of ACE2 in sepsis-induced cardiomyopathy (SIC) is still unexplored. In this study, our results revealed that CLP surgery dramatically impaired cardiac function accompanied with disruption of the balance between ACE2-Ang (1-7) and ACE-Ang II axis in septic heart tissues. Moreover, ACE2 knockin markedly alleviated sepsis induced RAS disorder, cardiac dysfunction and improved survival rate in mice, while ACE2 knockout significantly exacerbates these outcomes. Adoptive transfer of bone marrow cells and in vitro experiments showed the positive role of myeloid ACE2 by mitigating oxidative stress, inflammatory response, macrophage polarization and cardiomyocyte apoptosis by blocking NF-κB and STAT1 signals. However, the beneficial impacts were nullified by MasR antagonist A779. Collectively, these findings showed that ACE2 alleviated SIC by inhibiting M1 macrophage via activating the Ang (1-7)-MasR axis, highlight that ACE2 might be a promising target for the management of sepsis and SIC patients.

Advanced progress of the relationship between renin-angiotensin-aldosterone system inhibitors and cancers.

Hypertension and cancers are the most common causes of death in humans, as well as common co-diseases among elderly population. Studies have shown that hypertension is associated with carcinogenesis. The renin-angiotensin-aldosterone system (RAAS) is a crucial regulatory system of blood pressure, fluid, and electrolyte homeostasis, which plays an essential role in the pathogenesis of hypertension, whose mechanism is relatively clear. Studies have indicated that RAAS also widely exists in cancer tissues of different systems, which can affect the risk of cancers by stimulating cancer angiogenesis, participating in cancer-related oxidative stress, and regulating cancer-related immunity. Therefore, inhibiting RAAS activity seems beneficial to decreasing the risk of cancers. As one of the most commonly used antihypertensive drugs, RAAS inhibitors have been widely used in clinical practice. However, the conclusions of clinical studies on the relationship between RAAS inhibitors and cancers are not entirely consistent, which has been widely concerned by clinicians. The latest findings suggest that while RAAS inhibitors may reduce the risk of digestive cancers, respiratory cancers, urological cancers, gynecological cancers, and skin cancers, ACEIs may increase the risk of lung cancer, endometrial cancer, basal cell carcinoma, and squamous cell carcinoma. This article comprehensively reviews animal experiments, clinical studies, and meta-analyses on the relationship between RAAS inhibitors and cancers, to provide references for related studies in the future.

Effectiveness and safety of finerenone in diabetic kidney disease patients: a real-world observational study from China.

AIMS: Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). METHODS: Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. RESULTS: The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300-5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9-11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. CONCLUSIONS: This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.

Patiromer Facilitates Angiotensin Inhibitor and Mineralocorticoid Antagonist Therapies in Patients With Heart Failure and Hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is associated with suboptimal renin-angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. METHODS: Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). RESULTS: Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). CONCLUSIONS: In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in.

[GLP-1 receptor agonists : impact on diabetic kidney disease]. / Agonistes des récepteurs du GLP-1 : ­impact sur la maladie rénale diabétique.

In addition to optimal glycemic control and management of other factors aggravating the pathology (hypertension, dyslipidemia, -obesity), the cornerstone of treatment of diabetic kidney disease (DKD) includes blockers of the renin-angiotensin system, sodium-glucose cotransporter 2 inhibitors or nonsteroidal antagonists of the mineralocorticoid receptor (finerenone). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended in the treatment of high-risk patients with type 2 diabetes (T2DM) to reduce cardiovascular (CV) risk. Data from CV studies indicate a nephroprotective effect of certain GLP-1 RAs in T2DM patients with DKD. The FLOW study published in May 2024, analyzing the impact of semaglutide vs placebo on renal events as primary outcome, confirms this renal protection of GLP-1 RAs.

Outre le contrôle glycémique et la prise en charge d'autres ­facteurs d'aggravation de la pathologie, la pierre angulaire du traitement de la maladie rénale diabétique (MRD) comprend les bloqueurs du système rénine-angiotensine, les inhibiteurs du cotransporteur sodium-glucose de type 2 ou encore la finérénone (antagoniste de l'aldostérone). Les agonistes du récepteur du glucagon-like peptide-1 (ARGLP-1) sont recommandés dans le traitement des patients avec un diabète de type 2 (DT2) à haut risque afin de réduire le risque cardiovasculaire (CV). Les ­données provenant des études CV indiquent un effet néphro­protecteur de certains ARGLP-1 chez les patients DT2 avec MRD. L'étude FLOW, publiée fin mai 2024 et analysant l'impact du sémaglutide sur les événements rénaux comme critère principal, confirme cette protection rénale des ARGLP-1.

Role of Gut Microbiota in Dengue.

Dengue is a disease caused by a flavivirus (DENV) and transmitted by the bite of a mosquito, primarily the Aedes aegypti and Aedes albopictus species. Previous studies have demonstrated a relationship between the host gut microbiota and the evolution of dengue. It seems to be a bidirectional relationship, in which the DENV can affect the microbiota by inducing alterations related to intestinal permeability, leading to the release of molecules from microbiota dysbiosis that can influence the evolution of dengue. The role of angiotensin II (Ang II) in the microbiota/dengue relationship is not well understood, but it is known that the renin-angiotensin system (RAS) is present in the intestinal tract and interacts with the gut microbiota. The possible effect of Ang II on the microbiota/Ang II/dengue relationship can be summarised as follows: the presence of Ang II induced hypertension, the increase in angiotensinogen, chymase, and microRNAs during the disease, the induction of vascular dysfunction, the production of trimethylamine N-oxide and the brain/microbiota relationship, all of which are elements present in dengue that could be part of the microbiota/Ang II/dengue interactions. These findings suggest the potential use of Ang II synthesis blockers and the use of AT1 receptor antagonists as therapeutic drugs in dengue.

Sodium-glucose cotransporter 2 inhibitors and renin-angiotensin-aldosterone system, possible cellular interactions and benefits.

Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a newly developed class of anti-diabetics which exert potent hypoglycemic effects in the diabetic milieu. However, the evidence suggests that they also have extra-glycemic effects. The renin-angiotensin-aldosterone system (RAAS) is a hormonal system widely distributed in the body that is important for water and electrolyte homeostasis as well as renal and cardiovascular function. Therefore, modulating RAAS activity is a main goal in patients, notably diabetic patients, which are at higher risk of complications involving these organ systems. Some studies have suggested that SGLT2is have modulatory effects on RAAS activity in addition to their hypoglycemic effects and, thus, these drugs can be considered as promising therapeutic agents for renal and cardiovascular disorders. However, the exact molecular interactions between SGLT2 inhibition and RAAS activity are not clearly understood. Therefore, in the current study we surveyed the literature for possible molecular mechanisms by which SGLT2is modulate RAAS activity.

Renin-angiotensin system inhibitors and risk of hepatocellular carcinoma among patients with hepatitis B virus infection.

BACKGROUND: Hepatitis B virus (HBV) infection is a common cause of liver-related morbidity and mortality. Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) decrease liver fibrosis, an intermediate step between liver injury and hepatocellular carcinoma (HCC). Our aim was to investigate the association between the use of ACEIs and ARBs on incident HCC and liver-related mortality among patients with HBV infection. METHODS: We conducted a population-based study on a new-user cohort of patients seen at 24 hospitals across China. We included adult patients with HBV infection who started ACEIs or ARBs (ACEIs/ARBs), or calcium channel blockers or thiazide diuretics (CCBs/THZs) from January 2012 to December 2022. The primary outcome was incident HCC; secondary outcomes were liver-related mortality and new-onset cirrhosis. We used propensity score matching and Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of study outcomes. RESULTS: Among 32 692 eligible patients (median age 58 [interquartile range (IQR) 48-68] yr, and 18 804 male [57.5%]), we matched 9946 pairs of patients starting ACEIs/ARBs or CCBs/THZs. During a mean follow-up of 2.3 years, the incidence rate of HCC per 1000 person-years was 4.11 and 5.94 among patients who started ACEIs/ARBs and CCBs/THZs, respectively, in the matched cohort. Use of ACEIs/ARBs was associated with lower risks of incident HCC (HR 0.66, 95% CI 0.50-0.86), liver-related mortality (HR 0.77, 95% CI 0.64-0.93), and new-onset cirrhosis (HR 0.81, 95% CI 0.70-0.94). INTERPRETATION: In this cohort of patients with HBV infection, new users of ACEIs/ARBs had a lower risk of incident HCC, liver-related mortality, and new-onset cirrhosis than new users of CCBs/THZs.

Optimizing kidney and cardiovascular protection in an era of multiple effective treatments.

PURPOSE OF REVIEW: After decades of relying on the control of hypertension and treatment with renin angiotensin system inhibitors as the only evidence-based interventions to slow the progression of chronic kidney disease (CKD), we have entered an era when multiple effective treatment options are available. This review considers the mechanisms and benefits of these novel treatments as well as the challenges associated with achieving optimal combination therapy. RECENT FINDINGS: Over the past 5 years, large clinical trials have provided robust evidence that, when added to renin angiotensin system inhibitors, treatment with sodium glucose cotransporter 2 inhibitors reduces the rate of CKD progression and the risk of cardiovascular events in people with CKD with or without diabetes and with or without albuminuria; nonsteroidal mineralocorticoid antagonists and glucagon-like peptide-1 receptor agonists afford similar benefits in people with type 2 diabetes and CKD. The mechanisms of actions of these novel therapies suggest that combination therapy will produce additive benefits, though specific evidence is sparse. SUMMARY: Further trials are warranted to investigate the benefits of combination therapy with novel treatments in people with CKD. Clinical implementation of optimal combination therapy will require reorganization of services to ensure that patients receive adequate education, support and monitoring.

Clinical Properties and Non-Clinical Testing of Mineralocorticoid Receptor Antagonists in In Vitro Cell Models.

Mineralocorticoid receptor antagonists (MRAs) are one of the renin-angiotensin-aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs.

The Combination of Valsartan and Spironolactone Mitigated Mitral Regurgitation-Induced Cardiac Dysfunction in a Novel Rat Model.

ABSTRACT: Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin-aldosterone system inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction, its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/d), spironolactone (80 mg/kg/d), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared with that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced heart failure.

Time of day affects MrgD-dependent modulation of cardiomyocyte contractility.

The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. ß-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. NG-nitro-l-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling.NEW & NOTEWORTHY Alamandine, a member of the renin-angiotensin system, serves critical roles in cardioprotection, including the modulation of cardiomyocyte contractility. Whether this effect varies along the day is unknown. Our results provide evidence that alamandine via receptor MrgD exerts opposing actions on cardiomyocyte shortening, enhancing, or reducing contraction depending on the time of day. These findings may have significant implications for the development and effectiveness of future cardiac therapies.

Continuation vs Discontinuation of Renin-Angiotensin System Inhibitors Before Major Noncardiac Surgery: The Stop-or-Not Randomized Clinical Trial.

Importance: Before surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines. Objective: To evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery. Design, Setting, and Participants: Randomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France. Intervention: Patients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery. Results: Of the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes. Conclusions and Relevance: Among patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT03374449.

Cardiac Effects of Renin-Angiotensin System Inhibitors in Nonproteinuric CKD.

BACKGROUND: In contrast to proteinuric chronic kidney disease (CKD), the relative cardioprotective benefits of antihypertensive medications in nonproteinuric CKD are unknown. We examined long-term cardiovascular outcomes and mortality in patients with nonproteinuric CKD treated with renin-angiotensin system inhibitors (RASIs) versus other antihypertensive medications. METHODS: Among participants of the CRIC study (Chronic Renal Insufficiency Cohort) without proteinuria, we used intention-to-treat analyses with inverse probability of treatment weighting and Cox proportional hazards modeling to determine the association of RASIs versus other antihypertensive medications with a composite cardiovascular outcome (myocardial infarction, stroke, heart failure hospitalization, and death) and mortality. Secondary analyses included per-protocol analyses accounting for continuous adherence and time-updated analyses accounting for the proportion of time using RASIs during follow-up. RESULTS: A total of 2806 participants met the inclusion criteria. In the intention-to-treat analyses, RASIs versus other antihypertensive medications were not associated with an appreciable difference in cardiovascular events (adjusted hazard ratio [aHR], 0.94 [95% CI, 0.80-1.11]) or mortality (aHR, 1.06 [95% CI, 0.88-1.28]). In the per-protocol analyses, RASIs were associated with a lower risk of adverse cardiovascular events (aHR, 0.78 [95% CI, 0.63-0.97]) and mortality (aHR, 0.64 [95% CI, 0.48-0.85]). Similarly, in the time-updated analyses, a higher proportion of RASI use over time was associated with a lower mortality risk (aHR, 0.33 [95% CI, 0.14-0.86]). CONCLUSIONS: Among individuals with nonproteinuric CKD, after accounting for time-updated use, RASIs are associated with fewer cardiovascular events and a lower mortality risk compared with other antihypertensive medications. Patients with nonproteinuric CKD may benefit from prioritizing RASIs for hypertension management.

GLP-1RA vs DPP-4i Use and Rates of Hyperkalemia and RAS Blockade Discontinuation in Type 2 Diabetes.

Importance: Hyperkalemia is a common complication in people with type 2 diabetes (T2D) that may limit the use of guideline-recommended renin-angiotensin system inhibitors (RASis). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase urinary potassium excretion, which may translate into reduced hyperkalemia risk. Objective: To compare rates of hyperkalemia and RASi persistence among new users of GLP-1RAs vs dipeptidyl peptidase-4 inhibitors (DPP-4is). Design, Setting, and Participants: This cohort study included all adults with T2D in the region of Stockholm, Sweden, who initiated GLP-1RA or DPP-4i treatment between January 1, 2008, and December 31, 2021. Analyses were conducted between October 1, 2023, and April 29, 2024. Exposures: GLP-1RAs or DPP-4is. Main Outcomes and Measures: The primary study outcome was time to any hyperkalemia (potassium level >5.0 mEq/L) and moderate to severe (potassium level >5.5 mEq/L) hyperkalemia. Time to discontinuation of RASi use among individuals using RASis at baseline was assessed. Inverse probability of treatment weights served to balance more than 70 identified confounders. Marginal structure models were used to estimate per-protocol hazard ratios (HRs). Results: A total of 33 280 individuals (13 633 using GLP-1RAs and 19 647 using DPP-4is; mean [SD] age, 63.7 [12.6] years; 19 853 [59.7%] male) were included. The median (IQR) time receiving treatment was 3.9 (1.0-10.9) months. Compared with DPP-4i use, GLP-1RA use was associated with a lower rate of any hyperkalemia (HR, 0.61; 95% CI, 0.50-0.76) and moderate to severe (HR, 0.52; 95% CI, 0.28-0.84) hyperkalemia. Of 21 751 participants who were using RASis, 1381 discontinued this therapy. The use of GLP-1RAs vs DPP-4is was associated with a lower rate of RASi discontinuation (HR, 0.89; 95% CI, 0.82-0.97). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. Conclusions: In this study of patients with T2D managed in routine clinical care, the use of GLP-1RAs was associated with lower rates of hyperkalemia and sustained RASi use compared with DPP-4i use. These findings suggest that GLP-1RA treatment may enable wider use of guideline-recommended medications and contribute to clinical outcomes in this population.

Characterization of the circulating markers of the renin-angiotensin-aldosterone system in telmisartan- or enalapril-treated dogs with proteinuric chronic kidney disease.

BACKGROUND: Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. OBJECTIVES: To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. ANIMALS: Dogs with pCKD (n = 36) and healthy controls (n = 20). METHODS: Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. RESULTS: Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P < .001). Mean (95% confidence interval) percentage change from pretreatment value in serum Ang 1-7 concentration was significantly greater in telmisartan- (753% [489%-1134%]) versus enalapril-treated (149% [69%-268%]) dogs (P < .001). Serum aldosterone decreased with treatment (P = .02 for enalapril, P < .001 for telmisartan), with no difference between groups at day 30. CONCLUSIONS AND CLINICAL IMPORTANCE: Circulating RAAS activity is higher in dogs with pCKD. Compared with enalapril, treatment with telmisartan caused significantly greater increases in the presumed beneficial peptide Ang 1-7.