Treatment with the Type 2 diabetes medication metformin, lifestyle changes, or a combination of both, did not improve atrial fibrillation (AF) burden or progression when compared with standard care, according to preliminary late-breaking science presented at the 2024 American Heart Association (AHA) Scientific Sessions (16–18 November, Chicago, USA).
Previous research has indicated that lifestyle/risk-factor modification to reduce cardiovascular risk factors can help reduce AF burden—a quantitative term used to refer to the amount of time a person’s heart is experiencing the abnormal rhythms of AF. Additionally, researchers note that recent genomic and genetic studies have suggested that improving the biochemical levers handling metabolic stress—the response to stressors that can cause an imbalance in energy supplies to cells—might help AF patients.
“Interventions including weight loss, exercise and metformin act on an enzyme called AMP kinase, which is the master regulator of metabolic stress in the cells,” said lead study author Mina Chung (Cleveland Clinic, Cleveland, USA). “In this study, we examined whether interventions including these might reduce AF burden or progression.”
In this trial, dubbed ‘TRIM-AF’, 149 adults who had AF were randomly assigned to one of four treatment groups: standard of care (participants received educational pamphlets on healthy diet and exercise without individual counselling); a lifestyle/risk-factor modification programme (including referral to a preventive cardiology team for diet and nutrition counselling as well as for an exercise prescription and to address other cardiovascular risk factors); metformin only; or both the lifestyle/risk-factor modification programme and metformin. The patients in the lifestyle/risk-factor modification groups were offered a diet and exercise visit every three months in the first year of the study and every six months in the second year.
On average, patients in the metformin-only group, lifestyle/risk-factor modification group, and combination lifestyle/risk-factor modification and metformin group—but not the standard of care group—lost weight by the one-year follow-up but did not meet activity or fitness targets.
The study was open label, meaning both the researchers and participants knew which groups participants were in and which interventions they were receiving. Participants enrolled in the study had AF and an implanted cardiac device, such as a pacemaker or implantable cardiac defibrillator, to record daily AF burden or average percentage of time spent experiencing arrhythmia each day. Participants were followed for up to two years after enrolment in one of the four groups.
At the one-year follow-up, the analysis found:
- The AF burden decreased over time in the standard of care group, the lifestyle/risk-factor modification group, and the combination group. The metformin group initially tended to show worsened AF burden compared to standard of care, but at later time periods was not significantly different from baseline or standard of care.
- There were no significant differences in AF burden change between the four groups.
- The median baseline AF burden was 5.5% in the standard of care group, 1.8% in the metformin group, 2.1% in the lifestyle/risk-factor modification group and 6.5% in the combination group.
- At 9–12 months, median AF burden was 0.67% (relative change, –73.5%) in the standard of care group, 0.62% (relative change, –48.9%) in the metformin group, 0.13% (relative change, –85.9%) in the lifestyle/risk-factor modification group, and 0.9% (relative change, –72.4%) in the combination group.
- More than one third of the study’s participants in the two metformin groups either did not start or had to stop the medication due to gastrointestinal side-effects, including diarrhoea, nausea and stomach discomfort.
- All three intervention groups experienced weight loss (an average of 2.4% of their starting body weight in the metformin group, 2.1% in the lifestyle/risk-factor modification group and 4.4% in the combination group), while the standard care group did not significantly change (–0.5%).
- Neither of the lifestyle-modification groups—those taking metformin and those not taking it—achieved the target weight-loss goal (an average of 10% of participants’ starting body weight) and fitness targets (two-point metabolic equivalent [MET] improvement on stress testing) set for the study. Device-recorded physical activity times did not increase and fitness, assessed through exercise testing, showed no significant improvement.
- The researchers saw an improvement in AF symptom scores in the two lifestyle modification groups, which, according to Chung, reinforces how exercise and weight loss may help people feel better.
“We were especially surprised by the decrease in AF burden in the standard of care group,” Chung stated. “We analysed periods before randomisation and saw in all groups that the AF burden increased. Then, upon randomisation, we saw a decrease in AF burden in all groups.
“It is possible that the written [Cleveland Clinic] literature on diet and exercise we distributed to the standard of care group for participation in the study could have had a greater effect on reduction of AF burden than we thought. This was a group of patients who were motivated with discussions to join a lifestyle/risk-factor modification study. I think one of the key messages from this study is that talking to patients with AF about lifestyle/risk-factor modification, and giving them written instructions or more intensive individualised instructions, performed well.
“The metformin group also experienced a notably high rate of intolerance, which could have increased stress, and we do not know yet whether those who tolerated the metformin had other improvements. However, at this time, metformin alone should not be recommended as an upstream therapy for AF. The combination of metformin and lifestyle/risk-factor modification appeared to show some benefits, but these only reached levels similar to the standard of care arm.”
The researchers say will continue to analyse these data to determine if people who tolerated metformin and stayed on it for two years have a reduction in AF burden. They will also examine AF burden changes in people who had a higher AF burden when they enrolled in the study. According to Chung, another key message from this research is the importance of randomised studies that compare interventions.
“Prior, non-randomised studies have suggested a benefit of metformin in reducing AF; however, non-randomisation may have introduced bias,” she said.
The TRIM-AF study had several limitations, including its small size. In addition, the COVID-19 pandemic began in the middle of the study, which made it difficult to recruit participants and conduct in-person visits, according to the researchers. Chung noted that they adapted by changing the protocol to allow virtual visits and by reducing the sample size from 200 to 150 participants. The study will complete two-year follow-up in the autumn of 2025.