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Long-term metformin use and risk of pneumonia and related death in type 2 diabetes: a registry-based cohort study

Abstract

Aims/hypothesis

The long-term effects of metformin in individuals with type 2 diabetes who are at increased risk of severe respiratory infections are unknown. This study aimed to evaluate the effects of metformin use on the risk of first pneumonia hospitalisation and pneumonia-related death in a cohort of Chinese individuals with type 2 diabetes.

Methods

We performed a retrospective analysis of a consecutive cohort of 22,638 individuals with type 2 diabetes in the Hong Kong Diabetes Register enrolled between 2001 and 2018, with follow-up until 31 December 2019. Overlap propensity-score weighting was performed to balance baseline characteristics.

Results

Of 22,638 individuals with type 2 diabetes, after excluding those who had not been prescribed any glucose-lowering drugs (GLDs) and/or with eGFR ≤30 ml min−1 [1.73 m]−2 or treated by dialysis and/or treated with insulin at baseline, we identified 15,784 either prevalent or incident metformin users and 917 users of other GLDs during a mean follow-up period of 7.5 years. Overlap-weighted analysis showed an HR of 0.63 (95% CI 0.52, 0.77) for first pneumonia hospitalisation and 0.49 (95% CI 0.33, 0.73) for pneumonia-related death in metformin users vs users of other GLDs; similar observations resulted following stratification by sex and kidney function. There was also a negative association between metformin exposure over time (proportion of duration of metformin prescriptions during the total follow-up time) and pneumonia events using the penalised spline analysis. Metformin users had a lower neutrophil/lymphocyte ratio at first pneumonia hospitalisation vs non-metformin users (mean [95% CI]: 12.8 [12.1, 13.5] vs 14.8 [12.3, 17.3], p = 0.032). The rate of metformin-associated lactic acidosis was 2.5 per 100,000 person-years. The lower risk of pneumonia events was also observed among incident metformin users vs other GLD users.

Conclusions/interpretation

Long-term use of metformin was associated with reduced risk of pneumonia and pneumonia-related death among Chinese individuals with diabetes. The relevance of these results to other respiratory infections merits further investigation.

Graphical abstract

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Data availability

The data supporting the findings of this study are available on request from the corresponding author.

Abbreviations

CKD:

Chronic kidney disease

GLD:

Glucose-lowering drug

HKDR:

Hong Kong Diabetes Register

MSM:

Marginal structural model

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Acknowledgements

We acknowledge the Hong Kong Hospital Authority for providing the clinical data.

Authors’ relationships and activities

JCNC has received research grants and/or honoraria for consultancy and/or giving lectures from AstraZeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Hua Medicine, Lee Powder, Merck Serono, Merck Sharp & Dohme, Pfizer and Sanofi. APSK has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Merck Serono, Nestle, Novo Nordisk and Sanofi. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

AY was supported by the Impact Research Postdoctoral Fellowship of The Chinese University of Hong Kong.

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Authors

Contributions

AY and EC contributed to the conception of the article, statistical analysis and results interpretation, drafting of the manuscript and revising the manuscript critically, and approved the final version. MS, HW and ESHL contributed to results interpretation, revised the manuscript critically and approved the final version. RCWM, APSK and WYS contributed to conception of the article, revised the manuscript critically and approved the final version. AOYL and JCNC contributed to conception of the article and results interpretation, revised the manuscript critically and approved the final version. EC is the guarantor of this work, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Elaine Chow.

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Yang, A., Shi, M., Wu, H. et al. Long-term metformin use and risk of pneumonia and related death in type 2 diabetes: a registry-based cohort study. Diabetologia 64, 1760–1765 (2021). https://doi.org/10.1007/s00125-021-05452-0

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Keywords

  • Death
  • Diabetes
  • Metformin
  • Oral glucose-lowering drugs
  • Pneumonia