Metformin use by patients with stage 5 chronic kidney disease (CKD) may be an independent risk factor for early death, a Taiwanese study suggests.

In the retrospective study, investigators led by Chih-Cheng Hsu, MD, of the National Health Research Institutes, and Der-Deng Tarng, MD, of Taipei Veterans General Hospital in Taiwan, compared the mortality risk among 813 metformin users and 2,439 non-users who had type 2 diabetes and a serum creatinine level greater than 530 µmol/L (which is approximately the equivalent of stage 5 CKD). The researchers obtained 2000–2009 patient data from Taiwan’s national health insurance research database.

Although metformin, a biguanide, has been contraindicated for years in the United States and Europe for patients with advanced CKD, it has been prescribed to patients in Taiwan without renal contraindication until 2009.

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After a median follow up of 2 years, 53% of metformin users and 41% of non-users (controls) died. After adjusting for potential confounders, the researchers discovered that metformin use was associated with a significant 35% increased risk of mortality from all causes, according to findings published online ahead of print in The Lancet

The risk of premature death also increased with metformin dose: Compared with non-users, patients prescribed 501–1000 mg daily had a 30% increased risk, whereas those taking more than 1,000 mg daily had a 57% increased risk. Other factors, including other oral diabetes medications, a history of cardiovascular disease, age, and sex appeared to have no effect on mortality. Hypoglycemia also was not responsible, the researchers determined.

Metabolic acidosis, the main concern that has governed metformin’s contraindication, also appeared to have little impact. Upon analysis, the risk of metabolic acidosis between metformin users and non-users did not differ significantly. “Our results corroborate previous observations that no relevant link is present between metformin and lactic acidosis, even in patients with stage 5 chronic kidney disease,” the investigators stated. “Therefore, use of lactate concentrations to monitor and guide metformin treatment might not improve outcomes.”

In an accompanying editorial, Kamyar Kalantar-Zadeh, MD, MPH, PhD, and Connie M. Rhee, MD, of the University of California Irvine School of Medicine wrote, “Notwithstanding ongoing pressures from the endocrinology and nephrology communities to liberalise use of metformin in patients with CKD, the restrictions should be maintained, bearing in mind the utmost priority of practicing safe and conservative medicine.”

Future research is needed to determine the exact mechanisms by which metformin might increase mortality. Whether metformin at an appropriate dose can be continued in patients with less severe CKD remains unclear.


  1. Hung, S-C, et al. The Lancet; doi: 10.1016/S2213-8587(15)00123-0.
  2. Kamyar Kalantar-Zadeh and Connie M. Rhee. The Lancet; doi: 10.1016/S2213-8587(15)00133-3.