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Metformin May Increase Mortality in Advanced CKD among Type 2 Patients

Recent study reported a significant increase in all-cause mortality associated with the use of metformin in patients with type 2 diabetes…

Metformin is currently recommended as first line treatment for type 2 diabetes. However, its use is often limited in patients with chronic kidney disease stage 3 or higher due to the risk of lactic acidosis. According to Szu-Chun Hung, MD, from Taipei Tzu Chi Hospital, Taiwan, “studies examining the use of metformin in patients with advanced chronic kidney disease are lacking.” Therefore, Dr. Hung and his team performed a study to evaluate the safety of metformin use in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease.

Although metformin use is typically restricted in late stage chronic kidney disease, the regulations for metformin administration in type 2 diabetes are different across the world. Until June 2009, Taiwan was one of the few countries that allowed the administration of metformin in all type 2 diabetes patients regardless of severity for kidney disease. This allowed Dr. Hung and his team to conduct their study successfully in Taiwan.

In a retrospective, observational, cohort study, 813 metformin users with serum creatinine concentration greater than 530 micromol/L were selected from Taiwan’s national health insurance research database between Jan 1, 2000, and June 30, 2009, with follow-up data until Dec 31, 2009. Metformin users were matched with non-metformin users by propensity score in a 1:3 ratio. The two groups of participants were similar in baseline clinical and socioeconomic variables. The researchers’ primary outcome was all-cause mortality.

According to the results of the study, “All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. Metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20–1·51; p<0·0001).” Furthermore, the increased mortality risk was associated with higher dose and remained consistent across all subgroups. Finally, metformin users did not differ significantly from non-metformin users group in regard to risk of metabolic acidosis.

The finding of this study confirmed that metformin is associated with higher death rate among type 2 diabetes patient with higher stage of chronic kidney diseases. According to the authors of the study, “Our findings have important therapeutic implications, supporting the current recommendations that metformin should not be used in patients with stage 5 chronic kidney disease [serum creatinine > 5.3 mg/dL or estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2].” In addition, the researchers also recommended future study evaluating the use of metformin in patients with less severe chronic kidney disease.

Practice Pearls:

  • Metformin is not recommended in type 2 diabetes patient with chronic kidney disease stage 3 or higher due to risk for lactic acidosis.
  • Metformin users are associated with higher all-cause mortality rate when compared to non-metformin users (53% vs. 41%).
  • Metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20–1·51; p<0·0001).

Hung SC, Chang YK, Liu JS, Kuo KL, Chen YH, Hsu CC, Tarng DC. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinology. 2015 Jun 17. pii: S2213-8587(15)00123-0. doi: 10.1016/S2213-8587(15)00123-0.