Metformin associated with increased all-cause mortality risk in patients with type 2 diabetes and advanced CKD

Metformin is associated with higher risk for all-cause mortality in patients with type 2 diabetes and advanced chronic kidney disease (CKD), according to a recent study.

Most regulations, include those of the FDA, restrict use of metformin in patients with serum creatinine concentrations above certain levels, but there is currently debate about more widely prescribing the drug in patients with stage 4 or 5 CKD. Researchers in Taiwan, where metformin use was not restricted by creatinine concentration until 2009, performed a retrospective, observational cohort study of patients with type 2 diabetes and a creatinine concentration above 530 μmol/L, approximately the level that would indicate stage 5 CKD. Included patients were prospectively enrolled in Taiwan's national health insurance research database from Jan. 1, 2000, through June 30, 2009; follow-up data were available until Dec. 31, 2009. Patients who did and did not use metformin were matched by propensity score in a 1:3 ratio. The study's primary outcome was all-cause mortality. Results were published on June 17 by Lancet Diabetes & Endocrinology.

The researchers matched 831 metformin users to 2,439 nonusers, with a median follow-up of 2.1 years (range, 0.3 to 9.8 years). The primary outcome, all-cause mortality, was reported in 53% of metformin users and 41% of nonusers. Metformin use was found to be an independent risk factor for death after multivariate adjustment (adjusted hazard ratio, 1.35; P<0.0001), with a dose-dependent relationship. Metformin use was also associated with a higher risk for metabolic acidosis versus no metformin use, but this was not statistically significant (1.6 vs. 1.3 events per 100 patient-years; adjusted hazard ratio, 1.30; P=0.19).

The researchers noted that they were unable to adjust for some variables of interest, such as smoking history and diabetes care, and that they did not take potential changes in treatment regimens into account, among other limitations. However, they concluded that metformin is associated with a higher risk for all-cause mortality but not metabolic acidosis in patients with type 2 diabetes and stage 5 CKD. “Our findings have important therapeutic implications, supporting the current recommendations that metformin should not be used in patients with stage 5 chronic kidney disease,” they wrote.

The authors of an accompanying comment said that the study's findings leave little doubt that metformin is related to excess deaths in this patient population but noted that an argument could be made that withholding metformin from diabetic patients with CKD could have undesirable consequences, such as poor glycemic control, additional diabetes complications, and use of other agents with less favorable side effect profiles.

However, the comment authors said, the current study along with other data show that restricting metformin use in diabetic patients with CKD “has probably protected many patients from lactic acidosis, hypoglycaemia, and pancreatitis, and saved thousands of lives every year.” They concluded, “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.”