Using a sodium-glucose cotransport 2 (SGLT2) inhibitor instead of a dipeptidyl peptidase 4 (DPP4) inhibitor may reduce the risk of acute kidney injury (AKI) and AKI requiring dialysis in patients with type 2 diabetes, new study findings suggest.

Among 104,462 propensity-score matched patients (44.1% female; mean age 58 years) with type 2 diabetes treated with SGLT2 or DPP4 inhibitors in Taiwan’s 2016-2018 National Health Insurance Research Database, 856 patients (0.8%) experienced AKI and 102 patients (less than 0.1%) had AKI requiring dialysis over 2.5 years of follow-up.  

SGLT2 inhibitor users had significant 34% and 44% lower risks of AKI and AKI requiring dialysis compared with DPP4 inhibitor users, Chi-Jung Chung, PhD, China Medical University in Taichung, Taiwan, and colleagues reported in JAMA Network Open. The risks of AKI and AKI requiring dialysis were a significant 39% and 46% lower with dapagliflozin, respectively, and 30% and 41% lower with empagliflozin, respectively. Results for canagliflozin were not significant or not applicable.

Among potential causes of AKI, investigators documented heart disease, sepsis, respiratory failure, and shock in 22.7%, 23.6%, 6.5%, and 2.8% of patients, respectively. SGLT2 inhibitor use was significantly associated with a 58% lower risk of AKI among patients with respiratory failure and a 52% lower risk of AKI among patients with shock, the investigators reported. They found no relationship between AKI and heart disease or sepsis in the SGLT2 inhibitor group.

The risk of developing advanced chronic kidney disease (CKD) within 90 days of AKI was a significant 6.5% lower in the SGLT2 vs DPP inhibitor group, Dr Chung and colleagues reported. At baseline, 9.2% of patients had stage 1-3 CKD.

“Despite the warning of the US Food and Drug Administration Adverse Event Reporting System regarding the association between SGLT2i and the risk of AKI, an increasing number of clinical trials and clinical database studies have found that SGLT2i use was associated with a decreased risk of AKI,” Dr Chung’s team wrote.

The investigators suggested SGLT2 inhibitor use decreases intraglomerular pressure, podocyte stress, and proteinuria; improves renal cortical oxygenation; and reduces hypoxic injury through cellular signaling and decreased inflammation.

According to Dr Chung’s team, these findings suggest that SGLT2 inhibitors may be an effective way to prevent AKI and AKI requiring dialysis and improve outcomes.

Reference

Chung MC, Hung PH, Hsiao PJ, et al. Sodium-glucose transport protein 2 inhibitor use for type 2 diabetes and the incidence of acute kidney injury in Taiwan. JAMA Netw Open. Published online February 22, 2023. doi:10.1001/jamanetworkopen.2023.0453

Rajiv Agarwal, MD, from Indiana University in Indianapolis, and colleagues quantified the proportion of kidney and cardiovascular risk reductions seen during a 4-year period mediated by a change in kidney injury in a post-hoc analysis using pooled data from two phase 3 trials of finerenone. Data were included for 12,512 patients with CKD and type 2 diabetes who received finerenone and placebo (1:1 ratio).

The researchers found that the median urine albumin-to-creatinine ratio (UACR) was 514mg/g at baseline. Overall, 53.2 and 27.0% of patients in the finerenone and placebo groups, respectively, had a 30% or greater reduction in UACR. Eighty-four and 37% of the treatment effect on the kidney and cardiovascular outcomes, respectively, was mediated by a reduction in UACR (analyzed as a continuous variable). The corresponding proportions mediated were 64 and 26% when change in UACR was assessed as a binary variable (whether the 30% reduction threshold was met).

“The current results emphasize the importance of monitoring UACR after initiating treatment, as it can serve as a valuable surrogate indicator of the early treatment efficacy and offer insights into potential long-term kidney and cardiovascular benefits,” the authors write.

The study was funded by Bayer, the manufacturer of finerenone.

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HealthDay News — An aldosterone synthase inhibitor, BI 690517, reduces albuminuria, according to a study published online December 15 in The Lancet.

Katherine R. Tuttle, MD, from the University of Washington in Seattle, and colleagues enrolled adults with an estimated glomerular filtration rate 30 or greater and less than 90mL/min/1.73 m², urine albumin:creatinine ratio (UACR) 200 or greater and less than 5000mg/g, and serum potassium 4.8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Patients were randomly assigned to eight weeks of empagliflozin or placebo run-in. Participants were then re-randomly assigned to once-daily BI 690517 at a dose of 3, 10, or 20mg or placebo for 14 weeks. The change in UACR from the second randomization to the end of treatment was the primary end point.

Overall, 586 of the 714 run-in participants were randomly assigned to BI 690517 or placebo. The researchers found that the percent change in UACR was −3, −22, −39, and −37% with placebo and BI 690517 3-, 10-, and 20mg monotherapy, respectively. When added to empagliflozin, BI 690517 produced similar UACR reductions. In 10, 15, and 18% of participants receiving BI 690517 at doses of 3, 10, and 20mg, respectively, and in 6% of those receiving placebo, with or without empagliflozin, investigator-reported hyperkalemia occurred.

“Using BI 690517 along with empagliflozin may offer the potential for additive kidney protection, while mitigating hyperkalemia risk,” the authors write.

Several authors disclosed ties to pharmaceutical companies, including Boehringer Ingelheim, which is developing BI 690517 and funded the study.

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HealthDay News — The NoMicro classifier appears accurate for evaluating urine cultures in cases of suspected urinary tract infection in the primary care setting without the need for microscopy, according to a study published in the January/February issue of the Annals of Family Medicine.

Gurpreet Dhanda, MD, from the University of Kansas Medical Center in Kansas City, and colleagues redesigned a classifier (NoMicro) that does not depend on urine microscopy and retrospectively validated a machine learning prediction model for urine cultures internally (emergency department data set) and externally (primary care data set). Pathogenic urine culture growing 100,000 or greater colony-forming units was the primary outcome, while predictor variables were: age; gender; dipstick urinalysis nitrites, leukocytes, clarity, glucose, protein, and blood; dysuria; abdominal pain; and history of urinary tract infection.

The researchers found that removal of microscopy features did not severely compromise performance under internal validation (receiver operating characteristic area under the curve [ROC-AUC], 0.86 and 0.88 for NoMicro/XGBoost and NeedMicro, respectively). In external validation, excellent performance was also achieved (NoMicro/random forests ROC-AUC, 0.85).

“Retrospective simulation suggested that NoMicro/random forests can be used to safely withhold antibiotics for low-risk patients, thereby avoiding antibiotic overuse,” the authors write. “The NoMicro classifier appears appropriate for primary care. Prospective trials to adjudicate the balance of benefits and harms of using the NoMicro classifier are appropriate.”

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Overactive bladder treatment using antimuscarinic drugs increases the risks for urinary tract infection (UTI) and lower urinary tract symptoms (LUTS), a new study finds.

Nobuhiro Haga, MD, PhD, of Fukuoka University in Japan, and colleagues performed a meta-analysis of 29 placebo-controlled trials of antimuscarinic agents and 9 placebo-controlled trials of beta 3-adrenoceptor agonists involving 35,939 patients with overactive bladder, published during 2002 to 2021. All trials had low risk of bias.

At 1-3 months after treatment, UTI risk was a significant 23% higher among patients receiving antimuscarinic drugs compared with placebo, the investigators reported in The Journal of Urology. The broad UTI outcome encompassed upper UTI, acute cystitis requiring treatment, as well as febrile UTI. Use of antimuscarinic drugs also was significantly associated with a 2.9-fold increased risk for urinary retention (few patients required catheterization), dysuria, and/or increased residual urine volume, factors involved in UTI pathogenesis. Antimuscarinic drugs included imidafenacin, solifenacin, tolterodine, fesoterodine, darifenacin, and trospium of various doses.

Use of beta 3-adrenoceptor agonists was not associated with any of these risks, the investigators reported. Drugs in this class included solabegron, mirabegron, and vibegron.

“To prevent urinary tract infection emergence, beta 3-adrenoceptor agonists might be safer than antimuscarinic agents,” according to Dr Haga’s team. The investigators noted that UTI causes not only LUTS, but pyelonephritis, which can lead to kidney dysfunction. They suggested that older adults and patients with diabetes might be good candidates for beta 3-adrenoceptor agonists due to their increased risks for UTI. Women with strong overactive bladder symptoms and men without bladder outlet obstruction due to benign prostatic hyperplasia or other conditions might be good candidates for antimuscarinic agents.

The investigators acknowledged that a direct comparison between antimuscarinics and beta 3-adrenoreceptor antagonists in a randomized trial would be more reliable and informative than a meta-analysis.

Reference

Tsubouchi K, Arima H, Abe M, et al. Effect of pharmacotherapy for overactive bladder on the incidence of and factors related to urinary tract infection: a systematic review and meta-analysis. J Urol. 209(4):665-674. doi:10.1097/JU.0000000000003209

Treatment with aspirin might reduce mortality risk in patients with sepsis-associated acute kidney injury (SA-AKI) admitted to the ICU, investigators report.

In a propensity score analysis of 7694 adults with SA-AKI, the risk of dying within 90 days was 27.8% lower among those who received aspirin compared with those who did not, Fanna Liu, MD, and colleagues from The First Affiliated Hospital of Jinan University, in Guangzhou, China, reported in the Frontiers of Pharmacology. The median survival time was significantly longer for patients treated with vs without aspirin: 46.47 vs 24.26 days.

Hypertension, diabetes, and prior cardiac surgery are common in this population and each factor increases cardiovascular-related mortality. Aspirin use was associated with greater benefits in these patients. Aspirin significantly reduced the risk for early mortality by 33.3% in patients with prior cardiac surgery patients compared with 19.7% in patients without cardiac surgery. Patients with hypertension and diabetes had 24.2% and 28.2% lower mortality risk with aspirin use, respectively. Patients without these conditions had 24.1% and 21.2% reduced risks for early mortality, respectively.

Aspirin might exert beneficial effects on the cardiovascular system, the investigators suggested. In sepsis-associated AKI, aspirin may exert anti-inflammatory and anti-platelet effects. By AKI stage, patients with stage 3 AKI had the greatest 90-day mortality risk reduction (32.6%).

Dr Lui’s team also found a dose-dependent response. High-dose aspirin of more than 300 mg/d was significantly associated with a 14.8% reduced risk for early mortality compared with lower-dose aspirin. Enteric-coated aspirin appeared less effective than plain aspirin. High-dose aspirin inhibits both cyclooxygenase 1 and 2, whereas lower dose aspirin inhibits only 1 form of the enzyme.

ICU length of stay was significantly shorter for the aspirin than non-aspirin group: 5.19 vs 5.58 days. Gastrointestinal hemorrhage rates did not differ between patients taking vs not taking aspirin. “Aspirin may be an effective drug for SA-AKI,” according to Dr Liu’s team.

Previously, Avycaz had only been approved for adults and pediatric patients 3 months of age and older. The expanded approval was based on data from an open-label, single-arm, multicenter, phase 2 study (ClinicalTrials.gov Identifier: NCT04126031) that evaluated the pharmacokinetics, safety, and tolerability of Avycaz in 46 pediatric patients from birth (gestational age ≥31 weeks) to less than 3 months; the median age was 24 days. 

The overall safety profile of Avycaz in this pediatric population was similar to that seen in adults with cIAI, cUTI, and HABP/VABP. There was 1 death reported in the trial and no treatment discontinuations due to adverse reactions. The most common adverse reactions (incidence ≥3%) were vomiting and increased transaminases.

In this trial, 25 patients with suspected or confirmed bacterial infection received a single dose of Avycaz, while 21 patients with suspected or confirmed serious gram-negative infections received multiple doses. Among patients who received multiple Avycaz doses, the mean treatment duration was 6 days and the maximum treatment duration was 12 days.

Avycaz is supplied as ceftazidime 2g/avibactam 0.5g strength powder for IV injection in single-use vials.

HealthDay News — Cannabidiol (CBD) oil is safe but not effective for pain control or reducing opioid use in patients undergoing ureteroscopy with stent placement for urinary stone disease, according to a study published in the April issue of The Journal of Urology.

Gopal Narang, MD, from the University of North Carolina in Chapel Hill, and colleagues examined the effect of a US Food and Drug Administration-approved CBD oil (Epidiolex) on pain control and opioid use after ureteroscopy in a prospective double-blind trial. In total, 90 patients (median age, 64 years; 61% female) undergoing ureteroscopy with stent placement for urinary stone disease were randomly assigned to placebo or 20mg CBD oil for 3 days postoperatively in a 1:1 ratio.

The researchers found that the groups did not differ in pain scores or opioid usage postoperatively. When comparing physical activity, sleep, urination, and activities of daily life, the level of discomfort with ureteral stents was also not different between the groups. The groups did not differ in preoperative or perioperative characteristics.

“Postoperative CBD was safe but ineffective when compared to placebo in minimizing postureteroscopy stent discomfort or opioid usage,” the authors write. “Despite the availability of numerous analgesic agents, stent-related symptoms and bother continue to be a factor in patient care. Further translational research into the presence of endocannabinoid receptors in the ureter and studies evaluating CBD oil with dose escalation could help to better understand the role of CBD oil in the postureteroscopy setting.”

Several authors disclosed financial ties to the biopharmaceutical industry.

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The Food and Drug Administration (FDA) has accepted for Priority Review the New Drug Application (NDA) for cefepime-taniborbactam for the treatment of adults with complicated urinary tract infections (cUTI), including pyelonephritis.

Cefepime-taniborbactam is an investigational beta-lactam/beta-lactamase inhibitor (BL/BLI) antibiotic. The Company believes that the combination may provide another therapeutic option for difficult-to-treat drug resistant gram-negative bacteria, such as carbapenem-resistant Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa.

The NDA is supported by data from the pivotal randomized, double-blind, active-controlled, phase 3 CERTAIN-1 study (ClinicalTrials.gov Identifier: NCT03840148) that compared the efficacy and safety of cefepime-taniborbactam to meropenem in adults with cUTI, including acute pyelonephritis. Study participants were randomly assigned 2:1 to receive cefepime-taniborbactam 2.5mg intravenously (IV) every 8 hours or meropenem 1g IV every 8 hours for 7 days (up to 14 days for patients with bacteremia). 

The primary endpoint was the composite of clinical and microbiologic response (eg, bacterial eradication) at the test of cure (TOC) visit (days 19 to 23) in the microbiological intent-to-treat (microITT) population.

Findings showed that cefepime-taniborbactam met the primary endpoint achieving statistical noninferiority to meropenem at the TOC visit in the microITT population. Composite microbiologic and clinical success occurred in 70.6% of patients treated with cefepime-taniborbactam vs 58% of patients treated with meropenem (treatment difference 12.6%; 95% CI, 3.1-22.2). Moreover, cefepime-taniborbactam achieved statistical superiority to meropenem for the composite endpoint at TOC (2-sided P =.0088), which was sustained at the Late-Follow-Up visit (days 28-35).

Treatment-emergent adverse events occurred in 35.5% of patients treated with cefepime-taniborbactam and 29% of patients treated with meropenem. Serious TEAEs occurred in 2% of patients treated with cefepime-taniborbactam and 1.8% of patients treated with meropenem.

A Prescription Drug User Fee Act target date of February 22, 2024 has been set for this application.

“The NDA acceptance represents the culmination of unwavering dedication, scientific excellence, and the collaborative efforts of our talented team, partners, and clinical investigators,” said Christopher J. Burns, PhD, CEO of Venatorx. “Cefepime-taniborbactam exemplifies our commitment to innovation and improving patient outcomes. By addressing the evolving and increasing challenges posed by antimicrobial resistance, we aim to make a meaningful impact on global public health.”

Florian M. Wagenlehner, M.D., from Justus Liebig University in Giessen, Germany, and colleagues conducted a phase 3 randomized trial involving hospitalized adults with complicated UTI, including acute pyelonephritis. Participants were randomly assigned to receive intravenous cefepime-taniborbactam (2.5g) or meropenem (1g) every 8 hours for seven days in a 2:1 ratio; in the case of bacteremia, this duration could be extended up to 14 days.

The researchers found that composite success (microbiologic and clinical success on trial days 19 to 23) occurred in 70.6 and 58.0% of patients in the cefepime-taniborbactam and meropenem groups, respectively, with cefepime-taniborbactam superior to meropenem (treatment difference, 12.6 percentage points). At late follow-up (days 28 to 35), differences in treatment response were sustained, with higher composite success and clinical success seen for cefepime-taniborbactam. Adverse events occurred in 35.5 and 29.0% of patients in the cefepime-taniborbactam and meropenem groups, respectively; the 2 groups had a similar frequency of serious adverse events.

“Cefepime-taniborbactam was shown to be a potential treatment option for patients with complicated UTI and acute pyelonephritis caused by Enterobacterales species and P. aeruginosa, including antimicrobial-resistant strains,” the authors write.

The study was funded by VenatoRx Pharmaceuticals, the developer of cefepime-taniborbactam.

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Ylva Trolle Lagerros, MD, PhD, from the Karolinska Institutet in Stockholm, and colleagues used data from the Swedish Patient Register and the Prescribed Drug Register to examine the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication. Exposure was defined as 2 or more dispensed prescriptions of PDE5i.

The analysis included 55,777 men who were treated with nitrates and 5710 men treated with nitrates and a PDE5i. The researchers found that combined use of PDE5i treatment with nitrates was associated with increased mortality, cardiovascular mortality, noncardiovascular mortality, myocardial infarction, heart failure, cardiac revascularization, and major cardiovascular events (hazard ratios, 1.39, 1.34, 1.40, 1.72, 1.67, 1.95, and 1.70, respectively).

“Our goal is to underscore the need for careful patient-centered consideration before prescribing PDE5i medication to men receiving nitrate treatment,” senior author Daniel Peter Andersson, MD, PhD, from Stockholm University, said in a statement. “Furthermore, it justifies our efforts for continued research into the ambiguous effects of erectile dysfunction drugs on men with cardiovascular disease.”

One author disclosed ties to the pharmaceutical industry.

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