Metformin‐associated risk of acute dialysis in patients with type 2 diabetes: A nationwide cohort study

Abstract

Recent guidelines governing anti-diabetic medications increasingly advocate metformin as first-line therapy in all patients with type 2 diabetes. However, metformin could be associated with increased risk of acute kidney injury (AKI), acute dialysis and lactate acidosis in marginal patients. In a retrospective nationwide cohort study, a total of 168 443 drug-naïve patients with type 2 diabetes ≥50 years, initiating treatment with either metformin or sulphonyl in Denmark between 2000 and 2012 were included in this study (70.7% initiated treatment with metformin); calculation of 1-year risk of acute dialysis was based on g-standardization of cause-specific Cox regression models for acute dialysis, end-stage renal disease and death. One-year risks of acute dialysis were 92.4 per 100 000 (95% CI, 67.1-121.3) and 142.7 per 100 000 (95% CI, 118.3-168.0) for sulphonylurea and metformin, respectively. The metformin-associated 1-year risk of acute dialysis was increased by 50.3 per 100 000 (95% CI, 7.9-88.6), corresponding to a risk ratio of 1.53 (95% CI, 1.06-2.23), and a number needed to harm of 1988, thus providing evidence of potential concerns pertaining to the increasing use of metformin.

Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease

“…24 In contrast, information from a Danish national registry revealed that metformin use was associated with an increased risk of acute dialysis, among individuals with eGFR both above and below 60 mL/min/1.73m 2 . 25 An analysis of 813 Taiwanese patients with stage G5 CKD and matched controls also revealed a significant and dose-dependent increase in the risk of death among metformin users compared to controls and a non-significant increase in the risk of lactic acidosis. 26 In contrast, several recent studies found that metformin was associated with protective effects in individuals with CKD.…”

Association of Metformin Use With End‐Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay‐for‐Performance Program

“…Hsu et al reported that continual use of metformin was associated with a decline in the estimated glomerular filtration rate in patients with type 2 DM and moderate CKD. In a retrospective nationwide cohort study conducted in Denmark, Carlson et al indicated that the 1‐year risk of acute dialysis was 92.4 per 100 000 (95%CI, 67.1‐121.3) and 142.7 per 100 000 persons (95%CI, 118.3‐168.0) for sulphonylurea and metformin users, respectively, corresponding to a risk ratio of 1.53 (95%CI, 1.06‐2.23) and a number needed to harm of 1988. There are several possible explanations for the nephrotoxicity of metformin, including dehydration due to metformin‐related diarrhea, metformin‐associated lactic acidosis, metformin‐induced renal tubular damage, and renal mitochondrial dysfunction …”

“…A cohort study conducted in the United Kingdom indicated that patients receiving gliptin or glitazone monotherapy have a significantly higher risk of severe kidney failure than those receiving metformin monotherapy (adjusted hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.13‐5.74) . However, the use of metformin remains controversial because it has been demonstrated in other human studies to have a harmful effect on renal function, resulting in higher rates of acute dialysis and mortality . A lower risk of chronic dialysis when metformin was used (HR, 0.76; 95%CI, 0.69‐0.84) was reported, but the target population was a few patients with DM and advanced chronic kidney disease (CKD), which is indeed a contraindication for metformin use .…”

“…9 However, the use of metformin remains controversial because it has been demonstrated in other human studies to have a harmful effect on renal function, resulting in higher rates of acute dialysis and mortality. [10][11][12] A lower risk of chronic dialysis when metformin was used (HR, 0.76; 95%CI, 0.69-0.84) was reported, but the target population was a few patients with DM and advanced chronic kidney disease (CKD), 12 which is indeed a contraindication for metformin use. 6 Therefore, we conducted this retrospective nationwide cohort study in patients with DM without a history of kidney disease who were enrolled under the pay-for-performance (P4P) programs implemented by Taiwan's National Health Insurance Administration.…”

Could metformin be used in patients with advanced chronic kidney disease?

“…Many patients on metformin have comorbidities that increase the risk of lactic acidosis. Indeed, a recent retrospective study showed that, while metformin was significantly associated with an increased risk of the need for acute dialysis, this risk was conditional upon concomitant “patient frailty.” This implies that secondary characteristics that predispose a patient to enhanced lactate concentrations, such as age, renal function and cardiac failure, work in conjunction with metformin concentrations to induce damage.…”