Das, Ashesh

Background Primary aldosteronism (PA), a renin-independent state of aldosterone excess, is associated with excess risk of stroke, myocardial infarction, atrial fibrillation, heart failure, and chronic kidney disease compared with essential hypertension. Emerging evidence suggests that renin-independent aldosterone excess exists on a continuum rather than as a dichotomous disease state, including subclinical primary aldosteronism (sPA), even in normotensive individuals. Whether sPA is associated with major adverse cardiovascular events (MACE) prior to overt hypertension remains incompletely characterized. Objective To synthesize available evidence linking renin suppression and mild aldosterone excess to cardiovascular outcomes. Methods A narrative review of the literature was conducted using PubMed/MEDLINE, the Cochrane Library, and Web of Science from inception through May 2025, to identify cohort studies evaluating renin phenotype, aldosterone levels, and cardiovascular outcomes. Results Suppressed renin and higher aldosterone levels, even within conventionally normal ranges, are associated with incident hypertension, left ventricular hypertrophy (LVH), atrial fibrillation, and cardiovascular events. In overt PA, significantly higher rates of cardiovascular diseases have been observed compared with blood pressure-matched essential hypertension. Emerging population-based data suggest a graded cardiovascular risk extending below traditional diagnostic thresholds. Conclusion Biochemical phenotypes consistent with sPA may represent an early cardiometabolic state associated with elevated risk of MACE, even before overt PA criteria are met. The absence of standardized diagnostic thresholds and randomized interventional data currently limits clinical translation. Prospective trials evaluating renin-guided screening and early mineralocorticoid receptor antagonism are needed to determine whether intervention at the subclinical stage reduces long-term cardiovascular harm.

Background: Resistant hypertension represents a significant clinical challenge, often driven by dysregulated aldosterone production. Aldosterone synthase inhibitors (ASIs) are a novel therapeutic class designed to directly suppress aldosterone biosynthesis. This study aimed to synthesize evidence regarding the comparative efficacy, optimal dosing, and dose–response relationships of three ASIs—baxdrostat, lorundrostat, and osilodrostat—for the treatment of resistant hypertension. Methods: A systematic review and network meta-analysis (NMA) were conducted following PRISMA 2020 guidelines. We searched PubMed, Web of Science, and CENTRAL for randomized controlled trials (RCTs) published up to 31 October 2025. The primary outcome was the mean change in systolic blood pressure (SBP) compared to placebo. We utilized a frequentist random-effects model, characterized dose–response relationships via meta-regression, and ranked treatments using the Surface Under the Cumulative Ranking Curve (SUCRA). Results: The analysis included 8 RCTs comprising 3253 participants. Baxdrostat 2 mg once daily demonstrated the greatest antihypertensive efficacy with a mean SBP reduction of −13.8 mmHg (95% CI: −17.5 to −10.1) versus placebo, followed by Lorundrostat 100 mg (−12.5 mmHg) and Baxdrostat 1 mg (−11.5 mmHg). SUCRA analysis identified Baxdrostat as the highest-ranked treatment (83.0%), followed by Lorundrostat (67.8%) and Osilodrostat (55.5%). Dose–response meta-regression revealed strong linear correlations for Baxdrostat (R2 = 0.91), Osilodrostat (R2 = 0.81), and Lorundrostat (R2 = 0.80). Conclusions: ASIs, particularly Baxdrostat and Lorundrostat, offer robust blood pressure reductions in patients with resistant hypertension. The strong linear dose–response relationships suggest these agents have a favorable therapeutic window for titration. While effective, clinical implementation requires careful monitoring for adverse events.

e16443 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with KRAS mutations present in approximately 90% of cases. Patients with advanced or metastatic PDAC who have progressed after standard chemotherapy face limited treatment options, with historical outcomes showing objective response rates (ORR) below 10% and median progression-free survival (PFS) and overall survival (OS) of approximately 2-4 months and 6-8 months, respectively. The development of covalent KRAS G12C inhibitors—including sotorasib, adagrasib, garsorasib, glecirasib, and divarasib—has opened new therapeutic options for this molecularly defined subset of PDAC patients. Methods: We conducted a systematic review and meta-analysis of clinical trials evaluating KRAS G12C inhibitor monotherapy in patients with advanced/metastatic pancreatic ductal adenocarcinoma. Data were extracted from 3 studies (Strickler 2022, Li J 2025, and Tanios 2023) encompassing a total of 91 patients with KRAS G12C-mutant PDAC who had received 1-2 prior lines of chemotherapy. Pooled estimates were calculated using random-effects meta-analysis models (DerSimonian-Laird method). For proportion outcomes (ORR and DCR), standard errors were calculated using binomial distribution, and for continuous outcomes (PFS and OS), inverse-variance weighting was employed. Heterogeneity was assessed using the I² statistic and Cochran's Q test. All confidence intervals were calculated at the 95% level. Results: The pooled analysis revealed clinically meaningful efficacy across all endpoints. The pooled objective response rate (ORR) was 32.9% (95% CI: 17.0% to 48.9%), with moderate heterogeneity (I² = 64.0%). The pooled disease control rate (DCR) was substantially higher at 88.3% (95% CI: 80.5% to 96.1%), with low heterogeneity (I² = 27.7%), indicating consistent disease stabilization across studies. For survival outcomes, the pooled median progression-free survival (PFS) was 4.98 months (95% CI: 3.62 to 6.34 months), with low heterogeneity (I² = 32.3%). The pooled median overall survival (OS) was 8.73 months (95% CI: 6.07 to 11.39 months), though with substantial heterogeneity (I² = 77.0%). Conclusions: KRAS G12C inhibitor monotherapy demonstrates clinically significant and durable efficacy in pretreated adults with advanced/metastatic PDAC harboring the KRAS G12C mutation. The pooled ORR of approximately one-third, together with a DCR near 90%, indicates substantial tumor control in a population with historically poor outcomes. Median PFS of approximately 5 months and OS of nearly 9 months represent clinically relevant improvements over standard salvage therapies, supporting KRAS G12C inhibitors as a viable option after chemotherapy failure.