Severe Infection Outcomes With SGLT2 Versus DPP-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Active-Comparator Meta-Analysis of Real-World Cohorts.

In 30 seconds

This systematic review and active-comparator meta-analysis examined real-world severe infection outcomes among people with type 2 diabetes treated with SGLT2 inhibitors versus DPP-4 inhibitors. Eighteen cohorts were included, with 11 contributing to quantitative synthesis; all 11 were judged at moderate risk of bias. Pooled estimates were lower with SGLT2 inhibitors for incident pneumonia (ratio 0.65, 95% CI: 0.55-0.75) and sepsis (0.65, 0.53-0.80), but certainty was very low and heterogeneity substantial. The authors concluded that evidence did not suggest increased average infection risk, while cautioning that lower estimates do not establish prevention.

Key findings

• For incident pneumonia, the pooled ratio was 0.65 (95% CI: 0.55-0.75; prediction interval 0.45-0.93; I 2 = 89.8%; very low certainty).
• For incident sepsis, the exploratory pooled ratio was 0.65 (0.53-0.80; I 2 = 90.6%); its prediction interval crossed the null (0.38-1.13).
• Two cohorts reported identical unpooled estimates for infection-related hospitalisation: 0.74 each; certainty was low.
• Comparisons with GLP-1 receptor agonists showed no consistent lower-risk pattern across four cohorts.

Why it matters

Severe infections are clinically important outcomes when assessing glucose-lowering therapies. This synthesis provides comparative real-world evidence against an apparent increase in average severe infection risk with SGLT2 inhibitors versus DPP-4 inhibitors. However, substantial heterogeneity and very low certainty mean the lower pooled estimates should not be taken as evidence that SGLT2 inhibitors prevent pneumonia or sepsis.

What to keep in mind

The evidence came from observational cohorts, all quantitative cohorts were at moderate risk of bias, and estimates showed substantial heterogeneity with very low certainty for the co-primary outcomes.