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Peer-reviewedCC BY-NC 4.0Clinical Drug Investigation

Dose-Dependent Association of Long-Term Metformin Use and Diabetic Nephropathy Risk in Patients with Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Taiwan

  • Kuang-Hua Huang1,2
  • Shuo-Yan Gau3
  • Yu-Chia Chang4,5
  • Zong-Han Lin6
  • Tung-Han Tsai1
  • Ya-Lan Chang7,8
  • Chien-Ying Lee7,8
8 affiliations
  1. 1Department of Health Services Administration, China Medical University, Taichung, Taiwan
  2. 2Office of Research and Development, Asia University, Taichung, Taiwan
  3. 3Department of Medical Education, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
  4. 4Department of Long Term Care, College of Health and Nursing, National Quemoy University, Kinmen, Taiwan
  5. 5Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan
  6. 6School of Medicine, Chung Shan Medical University, Taichung, Taiwan
  7. 7Department of Pharmacology, Chung Shan Medical University, No.110, Sec.1, Jianguo N. Rd., Taichung, 40201 Taiwan
  8. 8Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
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Abstract

Background: Diabetic nephropathy (DN) is one of the most serious chronic microvascular complications of diabetes. Animal and clinical studies on the renoprotective effects of metformin have reported inconsistent results.

Objective: This study investigated the relationship between long-term metformin use and DN risk in patients with type 2 diabetes mellitus (T2DM), to determine whether this relationship exhibits a dose-dependent pattern.

Methods: This was a retrospective cohort study using data from a nationally representative database in Taiwan. Patients given a diagnosis of new-onset T2DM between 2002 and 2013 were divided into 2 groups: metformin and sulfonylurea treatment. We evaluated DN risk after a 5-year follow-up period. Using the Cox proportional hazard model, we estimated DN risk in correlation with the cumulative defined daily dose (cDDDs) of metformin, with adjustment for sex, age, income, urbanization level, diabetes severity, and various comorbidities.

Results: In the metformin-treated group, the DN incidence rates were 7.02%, 8.09%, 9.24%, and 10.75% for metformin administered at cDDDs of < 3 0, 30 to 120, 120 to 240, and > 240, respectively. After adjustments for relevant variables, relative to sulfonylurea-treated patients, patients who received metformin at cDDDs of < 30, 30 to 120, 120 to 240, and > 240 exhibited adjusted hazard ratios (95% CIs) for DN of 1.06 (1.03–1.09), 1.24 (1.21–1.27), 1.45 (1.41–1.49), and 1.72 (1.65–1.80), respectively.

Conclusions: In patients with T2DM, metformin treatment exhibited a dose-dependent relationship with an increased DN risk after 5 years of follow-up. Further large-scale prospective studies are warranted to confirm these findings and elucidate the biological mechanisms underlying this observed association.

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Cite

BibTeXRIS
BibTeX
@article{huang2026dosedependent,
  title = {{Dose-Dependent Association of Long-Term Metformin Use and Diabetic Nephropathy Risk in Patients with Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Taiwan}},
  author = {Kuang-Hua Huang and Shuo-Yan Gau and Yu-Chia Chang and Zong-Han Lin and Tung-Han Tsai and Ya-Lan Chang and Chien-Ying Lee},
  journal = {Clinical Drug Investigation},
  year = {2026},
  month = sep,
  doi = {10.1007/s40261-026-01594-4},
  url = {https://doi.org/10.1007/s40261-026-01594-4},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Dose-Dependent Association of Long-Term Metformin Use and Diabetic Nephropathy Risk in Patients with Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Taiwan
AU  - Kuang-Hua Huang
AU  - Shuo-Yan Gau
AU  - Yu-Chia Chang
AU  - Zong-Han Lin
AU  - Tung-Han Tsai
AU  - Ya-Lan Chang
AU  - Chien-Ying Lee
PY  - 2026
DA  - 2026/09/12
JO  - Clinical Drug Investigation
DO  - 10.1007/s40261-026-01594-4
UR  - https://doi.org/10.1007/s40261-026-01594-4
AB  - Background: Diabetic nephropathy (DN) is one of the most serious chronic microvascular complications of diabetes. Animal and clinical studies on the renoprotective effects of metformin have reported inconsistent results.  Objective: This study investigated the relationship between long-term metformin use and DN risk in patients with type 2 diabetes mellitus (T2DM), to determine whether this relationship exhibits a dose-dependent pattern.  Methods: This was a retrospective cohort study using data from a nationally representative database in Taiwan. Patients given a diagnosis of new-onset T2DM between 2002 and 2013 were divided into 2 groups: metformin and sulfonylurea treatment. We evaluated DN risk after a 5-year follow-up period. Using the Cox proportional hazard model, we estimated DN risk in correlation with the cumulative defined daily dose (cDDDs) of metformin, with adjustment for sex, age, income, urbanization level, diabetes severity, and various comorbidities.  Results: In the metformin-treated group, the DN incidence rates were 7.02%, 8.09%, 9.24%, and 10.75% for metformin administered at cDDDs of < 3 0, 30 to 120, 120 to 240, and > 240, respectively. After adjustments for relevant variables, relative to sulfonylurea-treated patients, patients who received metformin at cDDDs of < 30, 30 to 120, 120 to 240, and > 240 exhibited adjusted hazard ratios (95% CIs) for DN of 1.06 (1.03–1.09), 1.24 (1.21–1.27), 1.45 (1.41–1.49), and 1.72 (1.65–1.80), respectively.  Conclusions: In patients with T2DM, metformin treatment exhibited a dose-dependent relationship with an increased DN risk after 5 years of follow-up. Further large-scale prospective studies are warranted to confirm these findings and elucidate the biological mechanisms underlying this observed association.
SN  - 1173-2563
SN  - 1179-1918
ER  -