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.
Verbatim Formal Study Abstract
To update and methodologically refine the synthesis of real-world evidence on severe infection outcomes with sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i), emphasising limits of causal interpretation.
PubMed, Embase, Scopus and CENTRAL were searched from inception through 29 June 2026. Quantitative synthesis was restricted to DPP-4i active-comparator estimates. Incident pneumonia and sepsis were prespecified co-primary outcomes. Hazard ratios and incidence rate ratios were pooled as related but non-identical estimands using restricted maximum likelihood with modified Hartung-Knapp inference, with leave-one-out, prediction-interval and effect-measure-stratified analyses. ROBINS-I and GRADE were applied.
Eighteen cohorts were included; the 11 contributing quantitatively were all at moderate risk of bias. For incident pneumonia (five studies), the pooled ratio was 0.65 (95% CI: 0.55-0.75; prediction interval 0.45-0.93; I2 = 89.8%; very low certainty); omitting one multinational cohort whose follow-up began 2 years after drug initiation yielded 0.61 (0.56-0.67; I2 = 0%). For incident sepsis (five studies), the prediction interval crossed the null (0.38-1.13); the exploratory pooled ratio was 0.65 (0.53-0.80; I2 = 90.6%, and 88.1%-92.4% after every omission; very low certainty). Hazard-ratio-only point estimates were similar, although the sepsis estimate was imprecise (95% CI including 1.0). Two cohorts reported identical, unpooled estimates for infection-related hospitalisation (0.74 each; low certainty). Comparisons with GLP-1 receptor agonists did not show a consistent lower-risk pattern across four cohorts, two in selected populations, and randomised-trial syntheses have not shown a consistent class-wide preventive effect.
The available evidence did not suggest an increased average risk of severe infection with SGLT2i compared with DPP-4i. Given low to very low certainty and substantial heterogeneity, the lower pooled estimates should not be interpreted as a preventive effect.
PROSPERO: CRD420261390509.