medwireNews: First-line treatment with a sodium-glucose cotransporter (SGLT)2 inhibitor is associated with a significantly lower risk for delirium and all-cause mortality than treatment with metformin in adults with type 2 diabetes, real-world study findings indicate.
The data “support the inclusion of cognitive outcomes in diabetes treatment decisions and suggest a potential shift in first-line therapy strategies,” write Jiaqiang Zhang (People’s Hospital of Zhengzhou University, Henan, China) and co-authors in Diabetes Care.
They report that the cumulative incidence of delirium was 4.0% among 79,723 individuals (mean age 66 years, 56% men) from the TriNetX global health research network who initiated type 2 diabetes treatment with an SGLT2 inhibitor between 2005 and 2025.
By comparison, the delirium rate was 9.0% among 79,723 individuals, matched for demographics, clinical characteristics, laboratory measures, and medication use, who initiated metformin treatment during the same period. This gives an absolute risk reduction of 5.0%, which the researchers say corresponds “to a number needed to treat of 20, reinforcing the clinical relevance of our findings.”
After adjustment for potential confounders, SGLT2 inhibitor use was associated with a significant 9% lower risk for delirium relative to metformin use.
Of note, “[t]he divergence in delirium risk between the two groups became evident early in the follow-up period and continued to widen over time, suggesting a sustained protective effect of SGLT2 [inhibitors] against delirium development,” Zhang et al remark.
In addition, individuals in the SGLT2 inhibitor group had a significantly lower rate of all-cause mortality than those in the metformin group, at 6.5% versus 15.7%, which corresponded to a significant 15.0% lower risk for death in the adjusted analysis.
The researchers also carried out a series of subgroup analyses based on age, sex, race, medication use, and glycated hemoglobin (HbA1c) levels. These revealed that SGLT2 inhibitors offered some of the greatest protection against delirium among adults aged 80 years and older, for whom the risk was 17% lower versus metformin. There was no significant difference in delirium risk between the two treatment groups among younger participants.
Other subgroups that showed significant benefit with SGLT2 inhibitor use relative to metformin use included men (adjusted hazard ratio [aHR] for delirium=0.94), White patients (aHR=0.90), patients with better glycemic control (HbA1c 5.0–6.5%, 31–40 mmol/mol; aHR 0.91), insulin users (aHR=0.93), sulfonylurea users (aHR=0.72), and people using antiepileptic drugs (aHR=0.90) or sedatives (aHR =0.93).
“Given that insulin, antiepileptics, and sedatives are commonly used in high-risk populations for delirium, the greater risk reduction observed in these groups suggests that SGLT2 [inhibitors] may be particularly beneficial in preventing delirium among vulnerable patients,” write Zhang and co-authors.
They comment that although the 9% reduction in delirium risk overall may appear modest, “metformin itself has recognized neuroprotective properties, which may attenuate the relative difference.” Furthermore, “SGLT2 [inhibitor] users had lower mortality, meaning that they had more opportunity to develop delirium, potentially biasing results toward the null.”
The team concludes: “Given the far-reaching implications for clinical practice and public health, future trials should explore mechanistic pathways and long-term cognitive outcomes, ensuring that diabetes treatment is no longer just about glucose control but also about preserving brain health and quality of life.”
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