Background: Mineralocorticoid receptor antagonists can prevent cardiovascular events in patients with heart failure and non-severe chronic kidney disease, but their effects in patients with kidney failure requiring dialysis are uncertain. We aimed to assess the efficacy and safety of mineralocorticoid receptor antagonists in this patient population.
Methods: In this systematic review and meta-analysis, we updated our previous systematic review by searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature for randomised controlled trials published between database inception and March 18, 2025. Trials comparing a mineralocorticoid receptor antagonist with placebo or standard of care in adults (aged ≥18 years) receiving maintenance dialysis were eligible. Studies that did not report an outcome of interest (cardiovascular mortality, heart failure hospitalisation, all-cause mortality, all-cause hospitalisation, hyperkalaemia, gynaecomastia or breast pain, or hypotension) were excluded. Two reviewers independently identified studies, extracted data, and assessed the risk of bias using the Cochrane risk-of-bias tool. The main outcome was cardiovascular mortality assessed using the empirical Bayes random-effects models, stratified by risk-of-bias. The protocol is registered with PROSPERO (CRD420251008119).
Findings: 19 trials of steroidal mineralocorticoid receptor antagonists including 4675 participants met eligibility criteria. Effect estimates differed trials with low and high risk of bias. In four trials with a low risk of bias (n=3562), 264 cardiovascular deaths occurred in 1785 patients in the mineralocorticoid receptor antagonist group compared with 276 of 1777 patients in the control group (odds ratio 0·98 [95% CI 0·80-1·20]; I2=0·0%; τ2=0·0; moderate certainty) resulting in an absolute risk reduction of 1 fewer event per 1000 patients per year (95% CI 14 fewer to 11 more).
Interpretation: Our findings suggest that steroidal mineralocorticoid receptor antagonists have little to no effect on cardiovascular mortality in patients requiring dialysis. There is insufficient information on the effects of steroidal mineralocorticoid receptor antagonists in subgroups of patients requiring dialysis and no information on non-steroidal mineralocorticoid receptor antagonists. Future trials would need to consider the likelihood of only smaller effects or effects limited to patients or events with pathophysiology that is more clearly driven by aldosterone in their design.
Funding: None.
Background: ION224, a liver-directed antisense inhibitor of diacylglycerol O-acyltransferase 2 (DGAT2), suppresses de novo lipogenesis, an important metabolic pathway associated with lipotoxicity and the underlying inflammation, hepatocellular injury, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to prospectively assess the safety and efficacy of ION224 in patients with MASH and fibrosis.
Methods: ION224-CS2 was an adaptive, two-part, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial conducted at 43 clinical sites in the USA and Puerto Rico in patients aged 18-75 years with biopsy-confirmed MASH and fibrosis (stages F1, F2, and F3) and baseline liver steatosis ≥10%. In part 1, participants were randomly assigned (1:1:1) to subcutaneous injections of ION224 60 mg, 90 mg, or 120 mg, or placebo, once per month. In part 2, participants were randomly assigned (2:1) to ION224 90 mg and 120 mg or placebo after a pre-specified interim analysis of safety and efficacy (liver steatosis). The primary endpoint was ≥2-point reduction in Non-Alcoholic Fatty Liver Disease Activity Score Activity Score (NAS) with ≥1-point improvement in hepatocellular ballooning or lobular inflammation, and without worsening of fibrosis at week 51. The primary analysis was in a predefined per-protocol set that included patients who received at least ten of 13 doses of the study drug without missing three consecutive doses and completed the final liver biopsy at the end of treatment. ION224-CS2 was registered at ClinicalTrials.gov (NCT04932512) and is closed.
Findings: Between June 8, 2021, and Dec 27, 2022, 160 participants were randomly assigned to receive ION224 60 mg (n=23), 90 mg (n=45), or 120 mg (n=46), or placebo (n=46), of whom 123 were included in the per-protocol set. The primary endpoint was met in 18 (46%) of 39 participants in the 90-mg group (predicted risk 46·2% [95% CI 30·5-61·8]; risk difference 27·4% [95% CI 6·7-48·1], p=0·0094) and 20 (59%) of 34 in the 120-mg group (58·8% [42·3-75·4]; 40·1% [18·7- 61·4], p=0·0002) compared with six (19%) of 32 in the placebo group (predicted risk 18·7% [95% CI 5·2-32·3]). ION224 was safe and well tolerated. Adverse events were reported in 107 (94%) of participants treated with ION224 and 41 (89%) of 46 participants treated with placebo. There were no deaths and no treatment-related serious adverse events.
Interpretation: This study provides the first clinical evidence that antisense-mediated inhibition of DGAT2 with ION224 could be a safe and efficacious strategy for the treatment of MASH. The observed histological improvements were independent of changes in bodyweight, suggesting potential to combine with other therapies such as GLP-1 based treatments.
Funding: Ionis Pharmaceuticals.
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