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

Diabetologia. 2021 Aug;64(8):1760-1765. doi: 10.1007/s00125-021-05452-0. Epub 2021 Apr 12.


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.

Keywords: Death; Diabetes; Metformin; Oral glucose-lowering drugs; Pneumonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis, Lactic / epidemiology
  • Adult
  • Asian People / ethnology
  • Blood Glucose / metabolism
  • China / epidemiology
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality
  • Female
  • Follow-Up Studies
  • Glomerular Filtration Rate
  • Glycated Hemoglobin / metabolism
  • Hospitalization / statistics & numerical data
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Influenza Vaccines / administration & dosage
  • Lipids / blood
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Pneumococcal Vaccines / administration & dosage
  • Pneumonia / epidemiology*
  • Pneumonia / mortality
  • Prospective Studies
  • Registries
  • Risk Factors


  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Influenza Vaccines
  • Lipids
  • Pneumococcal Vaccines
  • hemoglobin A1c protein, human
  • Metformin