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.
4 affiliations
- 1Department of Pharmacy, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien City, Taiwan.
- 2Center for Clinical Epidemiology and Biostatistics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien City, Taiwan.
- 3Division of Infectious Diseases, Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien City, Taiwan.
- 4Tzu Chi University, Hualien City, Taiwan.
Abstract
Introduction
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.Methods
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.Results
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.Conclusions
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.Review registration
PROSPERO: CRD420261390509.
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BibTeX
@article{huang2026severe,
title = {{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.}},
author = {Yung-Ming Huang and Jen-Hung Wang and Wan-Ting Huang and Ji-Ze Hsu and Soon-Hian Teh},
journal = {Endocrinology, diabetes \& metabolism},
year = {2026},
month = nov,
doi = {10.1002/edm2.70381},
url = {https://europepmc.org/article/MED/42967597},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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.
AU - Yung-Ming Huang
AU - Jen-Hung Wang
AU - Wan-Ting Huang
AU - Ji-Ze Hsu
AU - Soon-Hian Teh
PY - 2026
DA - 2026/11/01
JO - Endocrinology, diabetes & metabolism
DO - 10.1002/edm2.70381
UR - https://europepmc.org/article/MED/42967597
AB - Introduction 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.Methods 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.Results 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.Conclusions 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.Review registration PROSPERO: CRD420261390509.
SN - 2398-9238
ER -