Cardiovascular and kidney benefits of <scp>GLP</scp> ‐1 receptor agonists across large randomized placebo‐controlled trials

Multiple large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have robustly shown that GLP-1 RAs lower the risk of major adverse cardiovascular events (MACE) in people with type 2 diabetes. Yet, two important knowledge gaps remain. First, previous CVOTs were dominated by injectable agents, leaving uncertainty about whether once-daily oral GLP-1 RAs confer comparable protection. Second, kidney benefits were inferred almost entirely from secondary endpoints of cardiovascular trials rather than from a kidney-specific outcomes study. The latest meta-analysis published by Lee et al.1 in Diabetes Care in 2025 presents the largest meta-analysis to date of cardiovascular and kidney outcomes with long-acting injectable and oral GLP-1 RAs in type 2 diabetes. Their study pools 10 trials (n = 71,351) and incorporates both the SOUL cardiovascular-outcome trial of oral semaglutide2- and the FLOW kidney-outcome trial of once-weekly semaglutide3 (Table 1). In the meta-analysis, across a median 3.2-year follow-up, long-acting GLP-1 RAs reduced three-point MACE by 14% (HR 0.86), hospitalization for heart failure by 14%, composite kidney events by 17%, and all-cause mortality by 12%, without new safety concerns. Earlier meta-analyses were dominated by injectable agents, leaving uncertainty over whether once-daily oral semaglutide could match them. Lee et al.1 found no heterogeneity across administration routes for any efficacy endpoint (between-group heterogeneity P = 0.984). This underscores the potential of oral GLP-1 RA therapy to deliver clinical ‘hard outcome’ benefits comparable with injectables, allowing treatment to be tailored to individual preference. However, the study also highlighted a permanent discontinuation rate of 25% in FLOW (injectable) and 27% in SOUL (oral). Discontinuation is influenced by patient preference, administration route, dosing frequency, convenience, and complexity, among other factors. Because oral semaglutide must be taken on an empty stomach with a small sip of water and followed by a 30-min fast, clinicians need to counsel patients carefully to optimize adherence. FLOW, the first GLP-1 RA trial that used a hard kidney endpoint as its primary outcome, showed a 24% risk reduction in kidney failure–centric events alongside an 18% reduction in MACE. Pooled with the other trials, the class achieved a 17% reduction in composite kidney outcomes, reinforcing GLP-1 RAs as renoprotective agents. The meta-analysis detected no increase in severe hypoglycemia, diabetic retinopathy, pancreatitis, or selected cancers versus placebo, consistent with prior safety reports. Effect sizes mirror those of earlier meta-analysis with fewer individuals or the one that includes SELECT trial4, a CVOT of semaglutide in people with obesity but without diabetes; the present work extends generalizability in three ways: inclusion of chronic kidney disease populations (FLOW); additional evidence that the efficacy of oral therapy is comparable to injectables, now with two oral GLP-1 RA trials (SOUL and PIONEER 6); and evidence that benefits persist against a background of contemporary multi-drug regimens (up to 19% concomitant SGLT2 inhibitor use in SOUL). First, current GLP-1 RA CVOTs are still dominated by participants with established cardiovascular disease. Apart from REWIND (31% with prior cardiovascular disease), every trial enrolled 52–100% patients with prior cardiovascular events. The ongoing ASCEND PLUS trial (NCT05441267) targets people with type 2 diabetes without previous cardiovascular disease and will directly address the question, ‘Can semaglutide prevent a first cardiovascular event?’ that is, primary prevention. Should the results be positive, they could broaden the drug's indication and influence future guidelines and clinical practice. Second, no completed randomized head-to-head cardiovascular or kidney outcome data exist comparing mono-incretin GLP-1 RAs with dual or triple agonists, such as tirzepatide; and evidence awaits SURPASS-CVOT (NCT04255433) and forthcoming trials. Third, we still do not have clinical biomarkers for the cardiovascular or renal benefits of GLP-1 RAs, let alone for dual- or tri-agonists. While we previously showed that HbA1c reduction is a pragmatic biomarker of three-point MACE in the pooled meta-regression analysis of GLP-1 RA CVOTs5, there is substantial heterogeneity at the individual level, potentially due to various reasons, including concurrent treatments, ethnicity, and other baseline characteristics. To move toward personalized treatment tailored to each person's profile, dissecting heterogeneity in the cardiovascular and renal efficacy of GLP-1 RAs warrants further study. By integrating the latest outcome trials, Lee et al.1 deliver robust evidence that long-acting GLP-1 RAs—including an oral option—confer clinically meaningful reductions in cardiovascular events, kidney disease progression, heart failure hospitalization, and death, without emergent safety issues. The availability of an oral formulation lowers practical barriers to earlier use, offering patients a choice of route without compromising cardiorenal protection. Future research will clarify their role in primary prevention, establish how they compare with emerging dual or triagonist therapies, and offer insights into factors influencing the heterogeneity of treatment response. Satoshi Yoshiji is supported by Canadian Institutes of Health Research (no.: 266602), McGill University (no.: 265215), and Japan Society for the Promotion of Science (no.: 202460267). Nobuya Inagaki has received scholarship grants from Sumitomo Pharma, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim; honoraria for lectures from Novo Nordisk Pharma, Sumitomo Pharma, Eli Lilly Japan, and Mitsubishi Tanabe Pharma; clinical commissioned/joint research grants from Asken. Satoshi Yoshiji has received consulting fees from the Broad Institute of MIT and Harvard through Precision Global Consulting as well as PriveBio, Inc. Approval of the research protocol: None. Informed consent: None. Registry and the registration no. of the study/trial: None. Animal studies: None. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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