A major comparative effectiveness study has found that three widely used glucagon-like peptide-1 receptor agonists (GLP-1 RAs) , Liraglutide, Semaglutide and Dulaglutide ; delivered broadly similar cardiovascular, kidney and mortality outcomes in people with type 2 diabetes, according to research published this month in JAMA Network Open.
Researchers analysed data from 21,790 veterans in the US Department of Veterans Affairs (VA) health system who started on one of the three GLP-1 RAs between January 2018 and December 2021. All participants were type 2 diabetics without end-stage kidney disease and were metformin-treated prior to initiation of the GLP-1 drug.
Of the cohort, 5,425 initiated liraglutide, 10,838 semaglutide and 5,527 dulaglutide. The average age was 63.5 years, over 90% were male, reflecting the veteran population studied.
Using weighted Cox regression models, the authors found no meaningful difference in the hazard of developing kidney failure (defined as sustained estimated glomerular filtration rate < 15 mL/min/1.73 m² or start of kidney replacement therapy) or in the composite “cardiovascular-kidney-metabolic” (CKM) outcomes , which included major adverse cardiovascular events (MACE: myocardial infarction, heart failure, or stroke/transient ischaemic attack) plus kidney failure , between the drugs. For instance, compared with semaglutide initiation, the hazard ratio (HR) for kidney failure with liraglutide was 0.93 (95% CI, 0.60-1.44) and for the CKM composite 0.96 (95% CI, 0.84-1.10).
Similarly, the risk of MACE was almost identical across the three treatments (HR for liraglutide vs semaglutide: 0.95; 95% CI, 0.83-1.09).
In terms of all-cause mortality, some differences emerged: in the intent-to-treat analysis, liraglutide was associated with a lower hazard of death compared with semaglutide (HR 0.83; 95% CI 0.69-0.99). Versus dulaglutide, liraglutide had a notably lower risk both in intent-to-treat (HR 0.69; 95% CI 0.58-0.83) and in the per-protocol analysis (HR 0.50; 95% CI 0.31-0.82). However, the authors caution these mortality differences may reflect confounding rather than true drug superiority.
Finally, in terms of gastrointestinal adverse events (such as gallstones or acute cholecystitis), the only statistically significant difference found was a reduced risk of gallstones (HR 0.72; 95% CI 0.54-0.95) and acute cholecystitis (HR 0.62; 95% CI 0.39-0.99) when comparing dulaglutide vs semaglutide.
The findings suggest that in a “real-world” veteran population initiating GLP-1 therapy, the three drugs are broadly equivalent when it comes to key outcomes of kidney failure and cardiovascular events. For clinical practice, this may reassure clinicians and patients that the choice among these agents might be guided by other factors (cost, tolerance, dosing convenience) rather than large differences in hard-end outcomes.
However, the authors stress that head-to-head randomised controlled trials would still be required to definitively establish whether any meaningful superiority or inferiority exists among the GLP-1 RAs for kidney or cardiovascular benefit.
Type 2 diabetes affects millions worldwide and is a major driver of both cardiovascular disease and chronic kidney disease (CKD). The interplay of metabolic, kidney and cardiovascular systems is increasingly conceptualised as the “cardiovascular-kidney-metabolic” (CKM) syndrome.
GLP-1 receptor agonists such as liraglutide, semaglutide and dulaglutide have already been shown in pivotal trials to reduce cardiovascular risk and delay kidney decline in patients with type 2 diabetes. For example, semaglutide is approved in the US to slow CKD progression among diabetics.
Against this backdrop, understanding whether the different GLP-1 RAs differ in their effectiveness becomes important , especially as generic versions and more widespread use are expected globally.
Although the study is drawn from a veteran cohort, the results offer relevant insights globally, where GLP-1 therapies are increasingly used not just for glycaemic control but for broad cardiometabolic benefit. The findings suggest that clinicians working within the National Health Service (NHS) may have flexibility in selecting among these treatments, with less concern about large outcome disparities between agents, though local cost, formulary and patient-specific considerations of course apply.
Moreover, with rising international interest in tackling CKD, diabetes and cardiovascular disease together, the study underscores the value of GLP-1 RAs as a core component in integrated care strategies. Nevertheless, translation to wider populations (including more women, younger patients and non-veterans) remains to be confirmed.
The authors acknowledge several important limitations: the retrospective observational design means that residual confounding is possible, and despite robust methods the observed mortality differences may reflect non-treatment differences rather than drug effects. The predominantly male, veteran cohort limits generalisability to broader populations. Also, while the “new user, active comparator” design is strong for observational research, it cannot fully replace randomised trials. Future research should aim for randomised head-to-head comparisons, and also assess longer-term kidney outcomes in more diverse patient groups.
In summary, this large observational study comparing liraglutide, semaglutide and dulaglutide in people with type 2 diabetes found broadly similar risks of kidney failure and cardiovascular events , offering reassurance that within this class of drugs, major outcome differences may be limited for many patients. Clinicians, including those in the NHS, may take comfort in these findings as they tailor treatment strategies , but should remain aware of the need for further direct comparative research.
Source:
Derington C.G., et al. “Liraglutide vs Semaglutide vs Dulaglutide in Veterans With Type 2 Diabetes.” JAMA Network Open. 2025. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2840010 JAMA Network
