Metformin discontinuation ups cardio-renal events in CKD patients with diabetes

Putting an end to the use of metformin may lead to a higher risk of cardio-renal events in patients with diabetes and advanced chronic kidney disease (CKD), regardless of their cardiovascular disease (CVD) status, suggests a study presented at ADA 2023.

On the other hand, “[c]ontinuation of metformin below estimated glomerular filtration rate (eGFR) 30ml/min/1.73m² may be associated with cardio-renal and mortality benefits that needs to be weighed against the risks of lactic acidosis,” said the researchers led by Aimin Yang, research assistant professor, Department of Medicine & Therapeutics Faculty of Medicine, The Chinese University of Hong Kong.

In this prospective, population-based study, Yang and colleagues included a total of 36,940 patients with diabetes in Hong Kong. They stratified the participants by metformin continuation within 6 months after reaching eGFR <30 ml/min/1.73m² in 2002‒2018 and followed them until 2019.

The researchers used a Cox model with time-dependent exposure and covariates to estimate the hazard ratio (HR) of death, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD) in a propensity-score overlap-weighed cohort of continued versus discontinued metformin users.

Some 8,400 (22.7 percent) metformin users with new-onset eGFR <30 ml/min/1.73m² stopped using the study drug within 6 months, while 28,540 (77.3 percent) continued the treatment. Among continued users, the median metformin daily dose was 1,000 mg. [ADA 2023, abstract 126-OR]

During a median follow-up of 3.5 years, incident MACE occurred in 15.3 percent of the participants, heart failure in 16.6 percent, and ESKD in 28.1 percent, while 41.5 percent died.

Compared with continued use of metformin, discontinuation significantly correlated with an increased risk of MACE (weighted and adjusted HR, 1.42, 95 percent confidence interval [CI], 1.31‒1.54), heart failure (HR, 1.70, 95 percent CI, 1.58‒1.83), ESKD (HR, 1.73, 95 percent CI, 1.63‒1.83), and death (HR, 1.24, 95 percent CI, 1.19‒1.29).

“Results were consistent in patients with and without established CVD,” said Yang and colleagues.

Fasting plasma glucose

Apart from these benefits, another study demonstrated that metformin use could reduce fasting glycaemia in patients with diabetes, independent of endogenous glucose production (EGP) reductions, by increasing the rates of aerobic glycolysis. [ADA 2023, abstract 222-OR]

This was shown by “increased peripheral glucose clearance and lactate production as well as reduced hepatic ATP content, which is consistent with metformin-induced inhibition of mitochondrial electron transport chain activity,” according to the investigators led by Theresia Sarabhai, research physician, German Center for Diabetes Research, Düsseldorf, Germany.

Sarabhai and her team found that metformin use did not affect the EGP rates but instead reduced the concentrations of fasting plasma glucose by 30 percent (p<0.01). This could be attributed to increased rates of glucose clearance (18 percent; p<0.005), which resulted in greater lactate production (p<0.01).

“These changes were associated with decreased hepatic ATP content (20 percent; p<0.05), increased hepatic glycogen content (40 percent; p<0.05), and no changes in hepatic TAG content,” the investigators said.