Metformin was recommended as first-line therapy for the treatment of T2DM, but until recently, its use was contraindicated in both T2DM and CKD patients due to the perceived risk of lactic acidosis. Accumulating evidence suggests that the incidence of lactic acidosis associated with metformin use is virtually indistinguishable from background rates in the overall diabetic population, leading to more liberal clinical guidelines allowing metformin use in patients with mild to moderate CKD. There has been controversy about whether metformin can be prescribed more widely in patients with advanced CKD, but until now, no studies have evaluated the benefits and risks of metformin use in these populations.A new cohort study published in TheLancetDiabetes&Endocrinology by Huang et al. from Taiwan showed that, compared with patients not using metformin treatment, there was a 35% increase in all-cause mortality in patients with advanced chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2DM) treated with metformin compared with those treated without metformin. The investigators used the National Health Insurance Research Database (NHIRD) in Taiwan to evaluate the safety of metformin use in patients with T2DM and in patients with serum creatinine levels >530umol/L (CKD stage 5). Data were obtained from patients enrolled between 2001-2009, before metformin was contraindicated in male patients with serum creatinine levels >133umol/L and female patients with serum creatinine levels >124umol/L, respectively, as prescribed by Taiwanese prescribing guidelines. Baseline serum creatinine and eGFR data were not available in NHIRD, so selection of patients with advanced CKD was extrapolated from patients prescribed erythropoiesis-stimulating agents in NHIRD with serum creatinine >530umol/L. The primary endpoints of all-cause mortality and the number of hospital admissions for lactic acidosis were evaluated. A total of 12,350 patients with T2DM and CKD stage 5 were identified from NHIRD during the study. In this cohort population, 1005 patients used metformin and 11345 patients did not. Patients were paired in a 1:3 ratio based on propensity scores, resulting in 813 metformin users and 2439 non-users. Baseline characteristics of patients were similar in both groups. In the paired cohort, 53% of metformin users died during follow-up compared to 41% of non-users. Further analysis suggested that metformin use was associated with a higher risk of cardiovascular disease admission prior to patient death compared with patients who were not prescribed metformin. After multifactorial correction, metformin use remained a significant independent risk factor for mortality, increasing the risk of death by 35% in patients with T2DM and advanced CKD. The increased risk of death by metformin was dose-dependent, with patients prescribed 501-1000 mg metformin per day having a non-significant increased risk of death, while those prescribed >1000 mg metformin per day had the highest risk. Metformin use was also associated with a higher but non-significant risk of lactic acidosis. The study was strong, including its nationwide representativeness of patient selection, statistical robustness, certainty of drug pellets, and documentation of comorbidities over the course of up to 9.8 years of follow-up. Despite continued pressure from the Endocrine Society and the Society of Nephrology to open up utilization of metformin in patients with CKD, restrictions on metformin use should be maintained, keeping in mind the highest priority for prescribing safe and conservative medications. The investigators note that while randomized controlled studies are needed to confirm or refute these results, it is less feasible to conduct clinical trials to test the safety of metformin use in patients with T2DM and advanced CKD. The results of this study further confirm previous observations in the literature showing no clear association between metformin and lactic acidosis, even at the stage 5 CKD stage. Further studies are needed to understand the precise mechanism of the increased risk of death associated with metformin use in these patients.