Incretin Mimetics and Cardiovascular Events—The Evolving Comparative Effectiveness Landscape
Year: 2025
Type: article
Abstract: Adverse cardiovascular events are by far the leading cause of premature mortality for adults with type 2 diabetes, and postmarketing randomized cardiovascular (CV) outcome trials of newly marketed glucose-lowering medications, as mandated by the US Food and Drug Administration, have demonstrated that compared with placebo, many incretin mimetics (including glucagon-like peptide-1 receptor agonists [GLP-1RA] and the glucose-dependent insulinotropic polypeptide/ GLP-1RA tirzepatide) confer substantial cardiovascular benefits in adults with type 2 diabetes and high CV risk.Incretin mimetics have revolutionized diabetes care and are used by a steadily increasing proportion of patients with diabetes.Clinicians often must decide which among many available incretin mimetics is best for a given adult with diabetes.American Diabetes Association guidelines support the use of incretin mimetics in patients with diabetes and atherosclerotic cardiovascular disease or high CV risk but do not indicate which incretin mimetic may be best for a particular patient.Because CV outcome trials vary in patient eligibility and outcome criteria, it is difficult to use these data to directly compare the CV benefits of specific GLP-1RA agents.In this study, Derington et al 1 provide new information on the comparative effectiveness of 3 GLP-1RA agents for cardiorenal outcomes and overall mortality in 21 790 veterans with diabetes and a wide range of CV risk who newly initiated treatment with semaglutide, liraglutide, or dulaglutide from January 1, 2018, to December 31, 2021.Results indicate that liraglutide and semaglutide have similar associations with a range of cardiorenal outcomes and overall mortality, while dulaglutide may be less beneficial and confer somewhat higher mortality risk.The results of this comparative effectiveness analysis of observational data, if credible, may provide useful information that clinicians can use to guide selection of GLP-1RA agents based on clinical objectives, treatment burden, and financial burden.Comparative effectiveness studies analyze observational data and use a range of sophisticated statistical methods-ideally grounded in a principled causal inference framework-to address confounding and other sources of bias. 2 Derington et al 1 describe a trial emulation framework, 3 a causal inference framework increasingly used to compare the effectiveness of different medications for important clinical outcomes.Such studies have several advantages over traditional clinical trials.First, results may be obtained quickly and at relatively lower expense.Second, evidence may be generalizable to a wide range of patients treated in clinical settings.Third, large sample sizes may support sophisticated assessment of heterogeneity of treatment effects and ultimately enable personalized estimation of treatment benefits and risks.Accurate assessment of the validity and clinical relevance of comparative effectiveness results depends on detailed reporting 4 of important elements of the study design and analyses because analytic decisions related to effect estimation may vary across studies and can greatly impact the causal interpretability of results. 2 Incorporating comparative effectiveness results into clinical guidelines is challenging and best done by a multidisciplinary team with specialized causal inference expertise.However, we propose that clinicians and others can begin to assess the validity and significance of a comparative effectiveness study by assessing the following key questions that, if properly addressed, increase confidence in the validity of conclusions: +
Source: JAMA Network Open
Authors: Patrick J. O’Connor, Romain Neugebauer
Institutions: HealthPartners, Kaiser Permanente
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
OpenAlex ID: W4415106372