Metformin + Lifestyle Changes for Atrial Fibrillation

(TRIM-AF Trial)

Overseen By Luke Laffin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Mina Chung, MD

Must not be taking: Metformin, Antiretrovirals, Topiramate, others

Disqualifiers: Heart failure, Renal disease, Alcohol, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the diabetes medication metformin and lifestyle changes can help patients with atrial fibrillation (AF), a condition where the heart beats irregularly. Participants will follow different plans: some will take metformin, some will focus on diet and exercise, and others will do both. The trial targets individuals with a pacemaker or similar device who have experienced AF episodes lasting at least 5 minutes in the last 3 months. Those with a device monitoring their heart and recent irregular heartbeats might be a good fit. As a Phase 4 trial, this research aims to understand how this already FDA-approved and effective treatment can benefit more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not be on metformin or certain other drugs like anti-retroviral protease inhibitors or topiramate. If you're on an antiarrhythmic drug, you should have been on a stable regimen for the past 3 months.

What is the safety track record for these treatments?

Research has shown that metformin is generally safe for people. Studies have linked it to a lower risk of developing atrial fibrillation (AF) in those with type 2 diabetes, suggesting it might be safe for AF treatment. Common side effects of metformin can include an upset stomach, but these are usually mild.

Lifestyle changes, such as improving diet and increasing exercise, are also safe. These changes have significantly reduced AF symptoms without major side effects.

Both metformin and lifestyle changes have been studied for their effects on AF. Although they have not significantly slowed AF progression compared to standard care, they are both considered safe options to try. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the combination of Metformin and lifestyle changes for atrial fibrillation because it targets the condition in a novel way. Unlike standard treatments that often focus on managing heart rate and rhythm with medications like beta-blockers or anticoagulants, this approach combines Metformin, a medication commonly used for diabetes, with lifestyle modifications such as diet and exercise. Metformin's potential role in reducing inflammation and improving metabolic function offers a unique angle in addressing atrial fibrillation. Additionally, incorporating lifestyle changes helps tackle underlying risk factors, potentially providing a more comprehensive strategy for managing this heart condition.

What evidence suggests that this trial's treatments could be effective for atrial fibrillation?

Research has shown that metformin, a common medication for type 2 diabetes, may lower the risk of developing atrial fibrillation (AF), a type of irregular heartbeat. It seems to work by affecting certain genes linked to AF and improving heart rhythm. Studies also suggest that lifestyle changes, such as regular exercise and a healthy diet, can significantly reduce the risk of AF, potentially cutting it in half. This trial will assign participants to different treatment arms, including metformin alone, lifestyle changes alone, or a combination of both, to evaluate their combined effects on AF risk. Further research is needed to confirm the potential additional benefits of combining metformin with lifestyle changes. ^{2 6 7 8 9}

Who Is on the Research Team?

Mina K Chung, MD

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

This trial is for adults with a pacemaker or ICD who've had at least one episode of atrial fibrillation in the past 3 months. They should not be on diabetes medication, have moderate renal disease, significant alcohol use, or life expectancy less than 2 years. Pregnant women and those unable to follow study protocols are also excluded.

Inclusion Criteria

You have a pacemaker or ICD with certain features for monitoring heart function.

You have not had atrial fibrillation recorded on your heart monitoring device in the past 6 months.

I have irregular heartbeats and plans to normalize it.

Exclusion Criteria

I am not pregnant, breastfeeding, or if capable of childbearing, I am willing to use contraception.

I have permanent atrial fibrillation and no plans to change it.

You drink more than two alcoholic drinks on average every day.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metformin extended release up to 750 mg twice daily and/or lifestyle and risk factor modification

3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in AF burden and other health metrics

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Lifestyle/Risk Factor Modification
• Metformin

Trial Overview The TRIM-AF study tests if Metformin and lifestyle changes can help manage Atrial Fibrillation in patients with cardiac devices. Participants will either get Metformin up to 750 mg twice daily or undergo lifestyle modifications, decided randomly.

How Is the Trial Designed?

Group I: Metformin + LRFM Experimental Treatment 2 Interventions

Metformin ER up to 750 mg twice daily + Lifestyle/Risk Factor Modification (LRFM) diet/nutrition, exercise, and risk factor modification

Group II: Metformin Experimental Treatment 1 Intervention

Metformin ER up to 750 mg twice daily

Group III: Lifestyle/Risk Factor Modification Experimental Treatment 1 Intervention

Lifestyle/Risk Factor Modification (LRFM): Diet/nutrition, exercise, and risk factor modification

Group IV: Control Active Control 1 Intervention

Written educational literature on healthy eating and exercise guideline

Group V: No Atrial Fibrillation Active Control 1 Intervention

Written educational literature on healthy eating and exercise guideline

Who Is Running the Clinical Trial?

Mina Chung, MD

Lead Sponsor

Trials

1

Recruited

180+

The Cleveland Clinic

Collaborator

Trials

1,072

Recruited

1,377,000+

American Heart Association

Collaborator

Trials

352

Recruited

6,196,000+

Published Research Related to This Trial

GLP-1 receptor agonists like liraglutide, dulaglutide, and semaglutide have been shown to significantly reduce the risk of major cardiovascular events in patients with type 2 diabetes at high cardiovascular risk, based on robust cardiovascular outcomes trials.

Current diabetes treatment guidelines emphasize the importance of using medications with proven cardiovascular benefits, such as GLP-1 receptor agonists, rather than solely focusing on blood sugar control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Outcomes Trials of Incretin-Based Therapies. Thethi, TK., Bilal, A., Pratley, RE.[2022]

A study of 405 patients with type 2 diabetes showed that both sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are safe to use alongside other glucose-lowering medications over a 12-month period.

The safety evaluation indicated no significant adverse effects on kidney function or liver enzymes, suggesting that these medications can be effectively integrated into standard diabetes treatment regimens without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Safety Profile of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists in the Standard of Care Treatment of Type 2 Diabetes Mellitus. Salmen, T., Bobirca, FT., Bica, IC., et al.[2023]

Long-acting GLP-1 receptor agonists, such as liraglutide and semaglutide, are effective anti-obesity medications that can lead to significant weight loss, with semaglutide showing an average weight loss of 11.6% after one year, compared to 5.5% with liraglutide.

Both medications are generally well tolerated, with similar safety profiles, though they can cause transient gastrointestinal issues; ongoing long-term studies are needed to further evaluate their efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit-Risk Assessment of Obesity Drugs: Focus on Glucagon-like Peptide-1 Receptor Agonists. Christensen, RM., Juhl, CR., Torekov, SS.[2020]

In a study of 2,853 adults with prediabetes, nearly 40% reported receiving recommendations from their healthcare providers to adopt healthier lifestyle changes, such as weight loss and increased physical activity.

Those who received counseling from healthcare providers showed higher adherence to lifestyle modifications, indicating that provider recommendations play a crucial role in encouraging healthier behaviors among individuals at risk for type 2 diabetes and cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of health care providers' recommendations for healthy lifestyle among U.S. adults with prediabetes. Yang, K., Lee, YS., Chasens, ER.[2019]

Citations

1. ahajournals.org ahajournals.org/doi/10.1161/CIR.0000000000000748

Lifestyle and Risk Factor Modification for Reduction of ... Recently, several studies have reported a positive impact on decreasing AF burden from lifestyle changes that target weight loss, physical ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11983686/

Lifestyle and risk factor modification in atrial fibrillation Respondents estimated that 70% of patients with AF at their institution may benefit from exercise-based cardiac rehabilitation but that only 10% are referred ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2772487524001090

Impact of lifestyle risk factors on atrial fibrillation The presence of multiple healthy lifestyle factors is associated with halving the risk of AF [45]. These findings emphasize the importance of addressing ...

4. academic.oup.com academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaf689/8243674

Improving outcomes of atrial fibrillation ablation by integrated ... Integrated lifestyle modification before catheter ablation reduces both repeat ablations and direct current cardioversions by half until 12 months after index ...

5. jacc.org jacc.org/doi/10.1016/j.jacc.2025.04.042

Catheter Ablation vs Lifestyle Modification With ... Despite important metabolic improvements associated with LFM, CA was superior to LFM combined with AADs in improving freedom from AF at 1 year in patients with ...

6. academic.oup.com academic.oup.com/europace/article/27/4/euaf075/8099191

Lifestyle and risk factor modification in atrial fibrillation In obese patients, weight loss ≥10% of body weight increases the likelihood of arrhythmia-free survival six-fold compared to weight loss <10%.11 Similarly, pre- ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11555354/

Impact of lifestyle risk factors on atrial fibrillation Both the development and progression of atrial fibrillation (AF) are affected by a range of modifiable lifestyle risk factors.

8. jamanetwork.com jamanetwork.com/journals/jamacardiology/fullarticle/10.1001/jamacardio.2025.4007?guestAccessKey=5999201f-963a-4783-a17b-8b527bf7c431&utm_source=fbpage&utm_medium=social_jamacard&utm_term=18536738703&utm_campaign=article_alert&linkId=872788382

Aggressive Risk Factor Reduction Study for Atrial ... We hypothesize that the aggressive and comprehensive LRFM will improve AF ablation outcomes. This study aims to evaluate the impact of ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022282824000890

The impact of lifestyle factors on atrial fibrillation Lifestyle modification is key to reducing AF incidence, burden and progression. Targets include weight loss, exercise, alcohol abstinence and smoking cessation.