Metformin Before Catheter Ablation for AF Helps Nondiabetic Patients With Overweight

NEW ORLEANS, LA—The diabetes drug metformin can reduce recurrence of atrial arrhythmia for patients with overweight and obesity undergoing catheter ablation even if they’re not diabetic, results from the META-AF trial suggest.

The randomized trial, recently presented at the American Heart Association (AHA) 2025 Scientific Sessions, found patients with body mass index (BMI) ≥ 25 kg/m² plus atrial fibrillation (AF) had a lower risk of recurrent atrial arrhythmia and decreased AF burden at 1 year after the procedure when they’d taken metformin in the 6 weeks leading up to ablation.

In META-AF, the drivers behind the drug’s benefits in this patient population aren’t clear, given that the metformin group didn’t experience large changes in either weight or glycemic control, say researchers.

“We have a couple of speculations about the mechanism of action,” investigator Amrish Deshmukh, MD (University of Michigan, Ann Arbor), said in an AHA press conference. Beyond the small but durable weight loss that’s seen with metformin, he said, the drug appears to have direct metabolic effects on cardiac myocytes that may ultimately stave off AF.

Usual care for AF includes lifestyle and risk factor modification, especially among patients with obesity, to promote cardiometabolic health as well as weight loss, Deshmukh pointed out. Prior observational and experimental studies have found metformin to be protective against AF, while randomized controlled trials of patients without diabetes have shown that use of the drug is associated with modest weight loss and decreases in LV mass.

“It’s well recognized that diabetes is a common and potent risk factor for atrial fibrillation. Elevated body mass index beginning at even the overweight category portends not only a higher risk of atrial fibrillation but progression of [AF] from paroxysmal to persistent to permanent forms,” said Deshmukh during the late-breaking presentation. High BMI also is linked to failure of catheter ablation, he noted.

The META-AF Trial

META-AF enrolled 117 patients with both persistent or paroxysmal AF and overweight or obesity who were slated to undergo catheter ablation, randomizing them to receive usual care including lifestyle education with or without metformin starting up to 6 weeks prior to their procedure.

Lifestyle education addressed weight loss, exercise, obstructive sleep apnea, tobacco use, and alcohol use. Metformin was titrated to the maximum tolerated dose. All patients were given a handheld ECG device (AliveCor; KardiaMobile) and told to record weekly in the absence of AF symptoms or daily starting the day after they received an automated diagnosis of AF.

After excluding patients who withdrew from the study or had changes to their planned ablation, the primary analysis included 99 patients (mean age 63 years; 70% male). Most (92%) had radiofrequency ablation, with 8% each having cryoballoon and pulse-field ablation. Approximately two in five had prediabetes. In the metformin group, the median dose was 1,000 mg twice daily. The level of rhythm monitoring was similar between the two study arms.

Atrial arrhythmia recurrence lasting more than 30 seconds between 3 and 12 months after a single ablation procedure, the study’s primary endpoint, was halved in the metformin group compared with usual care (HR 0.50; 95% CI 0.2-0.9). Freedom from recurrence was 78% with metformin versus 58% with usual care. Results also favored metformin in a post hoc analysis that used a 1-month blanking period after ablation.

AF burden, a secondary endpoint, also was lower with metformin than with usual care (8% vs 16% of days monitored; P = 0.02). “This finding should be interpreted in the context of antiarrhythmic medication use and repeat cardioversion or ablation,” both of which were more common—though not significantly so—in the control arm, Deshmukh cautioned.

Patients in each group lost weight and saw improvement in symptoms, with nonsignificant trends favoring metformin over usual care. Levels of HbA1c were similar between the two arms at baseline and 12 months.

Importantly, the single-center study was open label and did not assess long-term use of metformin, said Deshmukh. “However, we’re looking into the legacy effect after 1 year.”

A New Role for an Old Drug?

Discussant Gregory G. Schwartz, MD, PhD (Rocky Mountain Regional VA Medical Center and University of Colorado Anschutz School of Medicine, Aurora), started out his talk by asking: “Can an old dog learn new tricks?”

Metformin is “one of our oldest drugs,” dating back to use as an herbal remedy derived from French lilac in the 17th century, said Schwartz. Its clinical use to treat type 2 diabetes began in 1958, and more than 200 million people worldwide take it daily.

He explained that the drug is a weak inhibitor of Complex I of the electron transport chain, which induces an increase in adenosine monophosphate (AMP) that in turn activates AMP-activated protein kinase, an enzyme that acts as a cellular energy sensor. The latter “decreases anabolic and increases catabolic processes, thereby conserving energetics in the cell. It also activates a whole portfolio of cell protection and survival pathways,” Schwartz said.

In AF, atrial energy metabolism is perturbed, he continued. Metformin can sustain this metabolism under stress, reducing atrial and ventricular arrhythmias.

“So, in my opinion, the hypothesis underlying the META-AF trial has legs,” Schwartz commented. “The findings,” he added, “support further study of metformin as a potential anti-arrhythmic agent in larger, randomized, prospective trials.”