Treatment with glucagon-like peptide-1 receptor agonists was associated with an 11% reduction in serious infections compared with control groups, according to a systematic review and meta-analysis published in the Journal of Infection.
In an analysis of 136 randomized controlled trials involving approximately 164,000 participants, Shumeng Han, of the Department of Endocrinology at the Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, and the Diabetes Research Center of Chinese Academy of Medical Sciences in Beijing, China, and colleagues found that glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment was associated with reduced serious infection risk. More specifically, the relative risk (RR) was 0.89 and the absolute risk difference was −30 per 10,000 persons/year. Nonserious infections showed a similar reduction, as did total infections.
System-specific reductions were observed for serious respiratory infections (RR of 0.84), skin and subcutaneous infections (RR of 0.77), musculoskeletal infections (RR of 0.79), and vascular infections (RR of 0.65). Among 17 trials that included approximately 39,000 participants, GLP-1 RA treatment was associated with an 18% lower risk of serious COVID-19 infections.
Meta-regression analysis revealed that greater weight loss was significantly associated with reduced risk of serious infections and translated to a 1% lower relative risk per 1-kg weight decrease. Among trials in patients with diabetes (n = 106), hemoglobin A1c reduction showed a significant dose-dependent association with lower risk. Fasting blood glucose changes showed no significant association. Greater weight loss was also significantly associated with lower risk in subgroup analysis. Patients with weight loss greater than 3 kg showed an RR of 0.84 compared with 0.93 among those with weight loss of 3 kg or less. Hemoglobin A1c reduction also modified the association between GLP-1 RAs and infection risk. Patients with HbA1c reduction of 0.3% or less showed an RR of 1.06, those with HbA1c reduction between 0.3% and 0.7% showed an RR of 0.90, and those with HbA1c reduction greater than 0.7% showed an RR of 0.82.
Subgroup analyses demonstrated that high-dose GLP-1 RA treatment showed statistically significant risk reduction for serious infections (RR of 0.87), whereas low-dose treatment did not (RR of 0.98). Among individual agents, subcutaneous semaglutide (RR of 0.85) and tirzepatide (RR of 0.72) showed significant associations with reduced serious infection risk.
The study included trials published through September 24, 2024 and compared GLP-1 RAs with placebo or non-GLP-1 RA treatments. Most trials (79%) included patients with type 2 diabetes mellitus. The mean participant age was 56 years, with mean body mass index of 33 and mean HbA1c of 8%. Of approximately 164,000 total participants, about 92,000 received GLP-1 RAs and around 72,000 received placebo or active control.
Treatment duration, indication (type 2 diabetes vs weight loss), baseline body mass index, type of control group (placebo vs active comparator), and trial design (cardiovascular outcome trials vs others) did not modify the association between GLP-1 RAs and infection risk. No statistically significant differences were observed for serious urinary, gastrointestinal, cardiac, hepatobiliary, reproductive system, or nervous system infections.
"In a previous meta-analysis," the authors wrote, "we found no association of dipeptidyl peptidase-4 (DPP-4) inhibitors with infection risk, likely due to their weaker glucose-lowering and lack of weight-loss effects. Similarly, recent study has reported that GLP-1 RAs significantly reduce the risk of pneumonia and severe sepsis in patients with diabetes, while DPP-4 inhibitors do not. The superior weight loss and glucose-lowering effects of GLP-1 RAs suggest that these factors are crucial in reducing infection risk, or that GLP-1 RAs may exert direct anti-infection effects, which warrant further investigation." They added that GLP-1 RAs' immunomodulatory properties that combat proinflammatory responses, including cytokine storms, may be independent of reductions in glycemia or body weight. Reduction of "toll-like receptor-mediated inflammation through central nervous system GLP-1 receptor signaling" may also be another mechanism by which GLP-1 RAs can reduce infection risk, the authors described.
According to GRADE assessment, the certainty of evidence concerning GLP-1 RAs vs control groups on serious infections was high. For nonserious infections, total infections, and infections categorized as important medical events, certainty was moderate to high. For system-specific infections, certainty ranged from high to low. Sensitivity analyses—including iterative omission of each study, exclusion of all albiglutide studies, and application of fixed-effects models—showed unchanged pooled results. Publication bias testing indicated no significant bias for serious infections, though significant funnel plot asymmetry was observed for nonserious and total infections.
Study limitations included potential underreporting of infections because the studies included in the meta-analysis may not have been designed to evaluate infection outcomes. Detailed, individualized data and timing of infections were also not available, and subclassifications of infections were not performed.
Disclosures: The study was supported by the National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, National High Level Hospital Clinical Research Funding, and Beijing Municipal Natural Science Foundation. The researchers declared no competing financial interests or personal relationships that could have appeared to influence the work reported.
Source: Journal of Infection
