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CHICAGO -- Metformin with or without lifestyle modification did not reduce daily atrial fibrillation (Afib) burden over standard of care for patients with implanted heart devices, the randomized TRIM-AF trial showed.

In fact, treatment with twice-daily metformin trended worse early on for the primary endpoint -- a composite outcome measuring the amount of time patients experienced atrial arrhythmia during the trial, or death at 1 year -- while lifestyle/risk factor modification performed similarly to standard of care (written materials about a healthy diet and exercise).

While all four randomized groups showed improvements in Afib burden from baseline, reductions were greatest in the standard of care and lifestyle modification groups. Lifestyle modification was also associated with significant improvements in Afib symptom scores, reported Mina Chung, MD, of the Cleveland Clinic.

"We can't at this point recommend metformin for upstream therapy to reduce the burden of atrial fibrillation," she said at the American Heart Association (AHA) Scientific Sessions, adding that the researchers were "surprised" that they did not see a difference between the standard of care and lifestyle modification groups.

In explaining the rationale of the study, Chung noted that metformin has a favorable impact on the AMP-activated protein kinase, the master regulator of metabolic stress in cells, while caloric restriction and exercise are also known to beneficially affect AMP kinase. The researchers had reasoned that combining metformin with lifestyle modification could therefore reduce the stress on cells and result in improvements to Afib burden.

Starting in 2018, the randomized enrolled 149 patients with Afib and a permanent pacemaker (68.5%) or implantable cardioverter defibrillator (31.5%) at the Cleveland Clinic in Ohio.

Participants were assigned to one of four treatment groups: standard of care (pamphlets on lifestyle modification, diet, and exercise); lifestyle/risk factor modification alone; metformin alone at a twice-daily 750-mg dose; metformin and lifestyle modification combined.

Patients assigned to lifestyle modification met with an exercise physiologist and received an exercise prescription, met with a dietitian to get nutrition advice, and met with preventive cardiologist staff for other risk factor adjustments.

Participants had an average age of 74 years, 61% were men, and nearly all identified as white (97%). Nearly 80% had hypertension, while 38% had coronary artery disease and 9% a diagnosis of type 2 diabetes. There were more patients with hypertension in the groups that did not receive metformin (86.5% vs 72% in the groups that did).

The primary endpoint was a composite of change from baseline to 1 year of average daily Afib burden % after a 3-month blanking period -- assessed using data recorded by the implanted devices -- and survival at 1 year.

From baseline to months 9-12, median Afib burden changed as follows:

• Standard of care: 5.5% to 0.67% (relative change -73.5%)
• Lifestyle/risk factor modification alone: 2.1% to 0.13% (relative change -85.9%)
• Metformin alone: 1.8% to 0.62% (relative change -48.9%)
• Metformin and lifestyle modification combined: 6.5% to 0.90% (relative change -72.4%)

Chung said the researchers were surprised that Afib burden decreased with standard of care. They theorized that because lifestyle modification was discussed during trial enrollment for all patients, the standard of care group may have been motivated to follow the written suggestions to reduce Afib, which may have skewed the outcomes.

The metformin and lifestyle modulation groups showed significantly reduced weight during the trial -- ranging from 2.1% of body weight in the lifestyle modification group to 4.4% in the combination group -- though those amounts fell short of the trial's goal of 10%; the standard of care group lost a nonsignificant 0.5% of mean body weight. Exercise levels did not significantly change over the year, but many of the tests could not be performed due to COVID considerations, Chung said.

Janice Chyou, MD, of the Icahn School of Medicine at Mount Sinai in New York City, observed that patients in the lifestyle modification group reported feeling better -- "patients feel better when they lose weight and exercise."

"As with all good studies, there are often more questions that are raised," said Chyou, who was not involved in the research. She added that the trial is relevant because of the high burden of Afib in the population and suggested that the dose of metformin, the number of patients who discontinued metformin, and the age of the study participants may have had an impact on metformin's usefulness in the population.

Chung acknowledged that it was difficult to keep people on metformin, largely due to gastrointestinal side effects. There were two deaths in the metformin group before either person was given a dose, though these events were included in the intention-to-treat analysis.

Limitations included smaller enrollment due to the COVID pandemic (plan was 200 patients) and more virtual visits due to the pandemic. Two-year results of the ongoing trial will be presented at a later date.

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