Introduction: The overall evidence for the long-term exposure of metformin on cardiovascular-renal (CV) outcomes in patients with type 2 diabetes (T2D) at different stages of chronic kidney disease (CKD) remains controversial.

Methods: We conducted a prospective analysis of 14,766 Chinese patients with T2D enrolled between 2000 and 2016 observed until 31 December 2019. We compared all-cause mortality and incidence of major adverse CV events (MACE) and end-stage kidney disease (ESKD) in prevalent and new metformin users versus other glucose lowering drugs (GLDs) users stratified by CKD stage.

Results: During a mean follow-up of 9.6 years (141,310 person-years), we identified 1,798 deaths in metformin users (n=13,967) and 352 deaths in other-GLDs users (n=799). The mean daily dosage of metformin was 1,450 mg and duration of exposure was 7.8 years in CKD stage 1-2 (n=12,375). The respective figures were 1000 mg and 5.7 years in CKD stage 3-4 (n=1,592). Compared with other-GLDs, metformin exposure was associated with reduced risk of all-cause mortality (All: HR=0.48, 95% CI: 0.43-0.54; CKD stage 1-2: HR=0.38, 0.33-0.44; stage 3A: HR=0.53, 0.41-0.69); MACE (All: HR=0.85, 0.72-0.99; stage 1-2: HR=0.80, 0.65-0.99; stage 3-4: HR=0.97, 0.74-1.27) and ESKD (All: HR=0.65, 0.54-0.80; stage 1-2: HR=0.53, 0.33-0.85; stage 3-4: HR=0.80, 0.63-1.02). New users of metformin (n=4,013) had reduced risk of all-cause mortality across all CKD stages; MACE in stage 1-2 and ESKD in stage 1, 2 and 3 compared with users of other oral-GLDs (n=536). Increasing duration and dosage of metformin (up to 1500 mg/day) was associated with reduced or neutral risk of MACE, ESKD and all-cause mortality. The rate of metformin-associated lactic acidosis (MALA) was 5.39 per 100,000 patient-years in CKD stage 3-4.

Conclusion: Long-term metformin use was associated with reduced or neutral risk of all-cause mortality, MACE and ESKD among Chinese patients with T2D at CKD stage 1-3 with low risk of MALA.

Disclosure

A. Yang: None. E. S. H. Lau: None. H. Wu: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Luk: None. A. W. Fu: Research Support; Self; Merck KGaA. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis.

Funding

Asia Diabetes Foundation; Merck Pharmaceutical (HK) Limited; Chinese University of Hong Kong (to A.Y.)

© 2021 by the American Diabetes Association
2021
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