OLDER adults with type 2 diabetes experienced differing safety outcomes depending on the second-line antihyperglycaemic agents prescribed, according to a large multinational real-world study of 1.8 million patients.
As newer glucose-lowering therapies become more widely used, robust comparative safety data in older populations have remained limited.
This is particularly important given that adults aged ≥65 are more vulnerable to adverse drug events and are often underrepresented in clinical trials.
Antihyperglycaemic Agents Safety Varies by Drug Class
In this large cohort study spanning nine databases across the USA and Europe, researchers compared 18 safety outcomes across four major classes of second-line antihyperglycaemic agents. Advanced statistical methods, including propensity score adjustment and empirical calibration, were used to strengthen the reliability of findings.
The study found that both glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors were associated with significantly lower risks of hypoglycaemia and hyperkalaemia compared with sulfonylureas.
These findings are particularly relevant for older adults, in whom hypoglycaemia can lead to serious complications such as falls, hospitalisation, and cardiovascular events.
GLP-1 receptor agonists also demonstrated a lower risk of peripheral oedema compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, suggesting potential advantages in patients susceptible to fluid retention.
However, SGLT2 inhibitors were linked to an increased risk of diabetic ketoacidosis compared with both GLP-1 receptor agonists and sulfonylureas. Although relatively uncommon, this complication can be life-threatening and requires careful patient selection and monitoring.
Moving Towards Safer Prescribing Decisions
These findings highlight the importance of tailoring antihyperglycaemic therapy based not only on efficacy but also on safety, particularly in older adults with multiple comorbidities.
The scale and real-world nature of the study strengthen its clinical relevance, offering insights beyond those typically captured in controlled trials.
Nevertheless, as an observational study, the analysis may still be subject to residual confounding despite robust methodology. Additionally, variations in healthcare systems and prescribing practices across regions may influence outcomes.
Overall, the results support more informed, safety-conscious prescribing of antihyperglycaemic agents in older adults.
Future research is needed to further refine risk stratification and guide personalised treatment strategies in this growing and vulnerable population.
Reference
Kim C et al. Real-world evidence for comparative safety of second-line antihyperglycemic agents in older adults with type 2 diabetes. Nat Commun. 2026;DOI:10.1038/s41467-026-71307-0.
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