Metformin as an Upstream Therapy in Atrial Fibrillation
Phase: PHASE2
Conditions: Atrial Fibrillation
Sponsor: The Guthrie Clinic

Metformin as an Upstream Therapy in Atrial Fibrillation  
 
Protocol #GCIRB 1602-01 
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Protocol Title: 
 
 
 
Metformin as an Upstream Therapy in Atrial Fibrillation 
 
NCT02931253 
 
Version Date: January 23, 2018 
 

Metformin as an Upstream Therapy in Atrial Fibrillation  
 
Protocol #GCIRB 1602-01 
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Protocol Title: 
 
 
 
Metformin as an Upstream Therapy in Atrial Fibrillation 
 
Protocol #: 
 
 
 
 
GC IRB 1602-01 
 
Protocol Date:    
 
 
January 23, 2018 
 
Coordinating Center: 
Guthrie Medical Group P.C. and Robert Packer Hospital 
 
One Guthrie Square 
 
Sayre, PA  18840 
 
Principal Investigator: 
Pramod Deshmukh, MD 
Guthrie Medical Group P.C. 
One Guthrie Square  
Sayre, PA  18840 
 
SubInvestigator: 
Omar Waheed, MD 
 
Guthrie Medical Group, P.C. 
 
One Guthrie Square 
 
Sayre, PA  18840 
 
 
Zachary Wolfe, MD 
 
Guthrie Medical Group, P.C. 
 
One Guthrie Square 
 
Sayre, PA  18840 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Availability: 
Metformin hydrochloride (Glucophage®) 
 
Commercially available.   
 
 
 
 
Background:   
Atrial fibrillation (AF) is the most common arrhythmia and its prevalence is projected to rise with the 
increase in age and comorbid disease in the patient population. AF is associated with significant 
morbidity and a nearly doubled risk of death.1   
 
As such the development of therapies which prevent or slow the progression of AF is imperative.  
In randomized controlled trials of therapies for AF, pharmacologic maintenance of sinus rhythm has not 
been demonstrated to be superior to therapies to control ventricular rates.  In addition, medical therapy to 
maintain sinus rhythm was associated with significant cost and increased rates of hospitalization 3,4. 
However, in an "on treatment" analysis of the AFFIRM study which originally compared rhythm and rate 
control strategies, at an average of 3.3 years of follow up, the presence of sinus rhythm was associated 
with a significantly decreased risk of death (hazard ratio = 0.53)5. These findings suggest that the adverse 
effects of antiarrhythmic drugs in rate versus rhythm control studies offset the benefits of maintaining 
sinus rhythm when they are successful. Catheter ablation of the pulmonary veins and atria has been 
demonstrated to decrease the frequency of AF by 70-80% in several studies and provides a promising 
alternative to antiarrhythmic therapies.69  

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Obesity is a known risk factor for AF and weight reduction through caloric reduction and exercise has 
been demonstrated to decrease the duration and symptomatic burden of AF in overweight and obese 
individuals in a randomized controlled trial.10 In a recently published retrospective cohort study of a 
physician led weight management intervention, successful reduction of 10% of body weight was 
associated with a six-fold increase in arrhythmia free survival.11 Similarly, in a cohort study of overweight 
and obese patients undergoing catheter ablation for AF, a program of aggressive risk factor management 
prior to ablation led to improved glycemic control, blood pressure reduction, favorable left atrial 
remodeling and a nearly fivefold increase in AF free survival at two years with less use of antiarrhythmic 
medications.12  
 
Metformin hydrochloride (hereafter referred to as metformin) is the first-line pharmacologic therapy of 
Type II diabetes and has been associated with modest but sustained weight loss in diabetic individuals13,14. 
There has not been a randomized controlled trial to assess the weight effect of metformin on non-diabetic 
individuals who are overweight or obese. However in retrospective studies of metformin use in 
overweight and obese euglycemic individuals, metformin has been associated with modest weight loss 
(2.99.0 kg) without evidence of hypoglycemia.15,16  In a placebo controlled randomized controlled trial of 
metformin therapy of nondiabetic individuals with coronary disease and a large waist circumference, 
metformin use was associated with a 3.2 kg reduction at 18 months but did not improve other surrogate 
markers of cardiovascular disease.17The known gastrointestinal side effects of metformin therapy occurred 
with the expected frequency in these studies.  
  
In addition to obesity, there is significant epidemiologic and molecular data which implicates 
inflammatory, metabolic, and oxidative stress in the development and maintenance of AF. C-Reactive 
Protein (CRP) levels are known to be elevated in patients with AF and increasing CRP has been 
demonstrated to correlate with increasing AF burden.  Development of AF was associated with a shift 
from glycolytic to ketolytic metabolism.18   In genome wide transcriptional studies, patients susceptible to 
AF demonstrated decreased expression of sets of genes related to metabolic and oxidative stress 
responses.20    
  
Metformin acts by decreasing hepatic glucose production and increasing skeletal muscle uptake of blood 
glucose. These effects are thought to be in part mediated by metformin induced activity of AMP-activated  
protein kinase (AMPK) alterations in atrial calcium channels.21   In canine models of atrial fibrillation 
AMPK activation limits AF promoting22 In murine models of atrial fibrillation in which liver kinase B1, 
an activator of AMPK, is deleted, AF develops spontaneously in an age dependent manner and progresses 
from a paroxysmal to a persistent form in a similar manner to that seen in AF patients.23 Mutations in 
PRKAG2 gene, part of a subunit of AMPK have also been associated with early onset AF, and familial 
conduction diseases including Wolff-Parkinson-White syndromes.24 In transcriptional studies of human 
atrial fibrillation, AMPK subunit expression is increased in patients susceptible to AF but who remain in 
sinus rhythm while AMPK subunit expression is decreased in patients persistently in AF. This further 
suggests AMPK activity is protective in human AF.20  
  
Given the benefits of weight loss in AF, the benefit of metformin for weight loss, and the experimental 
and genetic evidence linking AMPK activation to metformin therapy and reduction in AF risk, the 
potential of metformin as an upstream therapy is promising.  
 
Trial Objective and Purpose: 

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The purpose of this trial is to determine if the upstream use of metformin in patients with atrial fibrillation 
and obesity undergoing a rhythm control strategy will increase the frequency of maintenance of sinus 
rhythm at six months. The primary endpoint is the number of patients in normal sinus rhythm after six 
months of follow up. Secondary endpoints are amount of weight loss, change in BMI, change in 
hemoglobin A1c, number of thromboembolic events, and burden of atrial fibrillation based on the Atrial 
Fibrillation Severity Score (AFSS). 
 
Trial Design:  
The proposed study will be a randomized control trial comparing metformin therapy  to a control group in 
patients with a BMI ≥27 and atrial fibrillation who have elected to undergo a rhythm control strategy with 
ablation. Upstream therapy with Metformin will be used in a randomized fashion. The only variation to 
the standard of care will be the addition of Metformin therapy and additional blood draws for safety 
monitoring and EKGs for measuring outcomes in both the intervention and control groups.  
  
Patients meeting the below inclusion and exclusion criteria who provide informed consent will be 
randomized to control versus metformin therapy six weeks prior to rhythm control. 
 
At baseline all study patients will be assessed for:  
Age, Gender, Weight, BMI, Tobacco Use, Hypertension, Hemoglobin A1c, Hyperlipidemia, serum 
CRP, glomerular filtration rate estimating equation (eGFR), B12, liver function tests (AST, ALT, 
ALP, bilirubin, albumin, INR), lactic acid, History of Coronary Artery Disease by MI, PCI, or CABG, 
History of Valvular Disease, History of Obstructive Sleep Apnea, Type of AF and duration, Number 
of Antiarrhythmic Medications  (not including beta-blockers or calcium channel blockers). 
 
In addition, patients will fill out a survey to determine their Atrial Fibrillation Severity Score (AFSS) – a 
validated tool to assess the symptomatic burden of AF - and will receive education on dietary changes and 
exercise. 
 
Metformin will be initiated at 500 mg daily and increased as tolerated to 2000 mg daily over a three week 
period. Subjects will be instructed to hold Metformin on the day of any procedure or study requiring the 
administration of intravenous contrast and to resume 48 hours after the contrast administration and 
reinstituted only after renal function has been reevaluated and found to be at the patient’s baseline. All 
patients will receive information on dietary changes to promote weight loss and will be encouraged to 
increase exercise activities. Patients will discontinue treatment at any time they are found to meet the 
baseline exclusion criteria for the study.  
 
The initiation of the drug and the dosage increases will be overseen by a designee (mid-level cardiology 
practitioner) who will be responsible for stopping dosage increases if side effects occur. Six  
weeks after the initiation of drug the patient will undergo ablation with the intent of achieving rhythm 
control. 
 
Patients will be followed up in regular intervals after the initial attempt at rhythm control. The minimum 
follow up interval is every three months. More frequent follow up may be scheduled as deemed necessary 
by the treating physician.  
 
At the time of the first attempt at rhythm control, at the 3 month follow up, and at the 6 month follow up 
all study patients will be assessed again for:  

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Weight, BMI, Hemoglobin A1c, serum CRP, eGFR, liver function tests (AST, ALT,  
ALP, bilirubin, albumin, INR), B12, lactic acid, number of antiarrhythmic agents, presence of AF 
by EKG, and Atrial Fibrillation Severity Score. 
 
At each 3-month and 6-month follow up, data will be reviewed by a designee who will use the criteria 
described below for reporting to the Medical Monitor. The patient will also be assessed for the occurrence 
of any adverse events as defined below and adverse events will be reported to the medical monitor. 
 
At the end of 6 months of therapy, the decision to continue Metformin beyond 6 months will be made in 
conjunction with the patient’s treating cardiologist and primary care physician.  
 
Figure 1. 
 
 
 
 
Investigational Product: 
Subjects with: 1) Atrial fibrillation undergoing rhythm control by  
ablation 
                                    2) BMI ≥ 27  
Metformin Group 
 
Metformin 500 mg daily 
initiated 6 weeks prior to 
scheduled ablation 
 
Metformin increased to 2000 
mg daily (1000 mg twice a 
day) as tolerated over the 
initial 3 weeks (See Figure 2) 
 
Study Schema 
1:1 Randomization 
Control Group 
 
 
Ablation only (standard 
of care) 
Education on dietary changes and exercise 
Completion of Atrial Fibrillation Severity Score Survey 
Follow Up 
At 3 months and 6 months after ablation: patients assessed for Weight, 
BMI, HbA1c, serum CRP, eGFR, B12, hepatic function, number of 
antiarrhythmic agents, presence of AF by EKG and Atrial Fibrillation 
Severity Score. 
 

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An investigational product is defined a pharmaceutical form of an active substance or placebo being 
tested or used as a reference in a clinical study, including products already with a marketing authorization 
but used or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
 
In this protocol, the investigational product is: GLUCOPHAGE® (metformin hydrochloride) tablets. 
The investigational product is available commercially.  The outpatient pharmacy will obtain the 
investigational product.  
The investigational product will be stored in a secure area according to local regulations. The investigator 
will ensure that investigational product is only dispensed to study subjects.  
 
Storage and Dispensing: 
The study drug is commercially available.  Study drug will be stored in accordance with the package 
insert at 20°–25° C (68°–77° F); excursions permitted to 15°–30° C (59°–86° F).  
 
Investigational product documentation will be maintained that includes all processes required to ensure 
drug is accurately administered. This includes documentation of drug storage, administration and storage 
temperatures. 
 
Per package insert:  The usual starting dose of GLUCOPHAGE® Tablets is 500 mg twice a day or 850 
mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 
850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses.  
 
In this study the starting dose will be 500 mg daily, given with meals.  Over a 3 week period, the dosage 
will be increased to 2000 mg daily (given in a divided dose of 1000 mg twice a day) as tolerated by the 
patient, according to the schedule below.  
 
Figure 2. 
 
Study Drug 
Week  1 
Week 2 
Week 3 
Week 4 
Number of pills in Morning   
1 
1 
2 
2 
Number of pills in Evening   
0 
1 
1 
2 
Total pills per day 
1 
2 
3 
4 
Daily dose  
(of 500 mg tablet) 
500 mg 
1000 mg 
1500 mg 
2000mg 
 
 
 
 
 
Method of Assigning Subject Identification: 

Metformin as an Upstream Therapy in Atrial Fibrillation  
 
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The study design is a randomized control trial.  After the subject’s initial eligibility is established and 
informed consent has been obtained, the subject will be enrolled into the study by obtaining a randomly 
assigned subject number.  The subject number will determine the randomization to the treatment or 
control arm.  
 
Selection and Withdrawal of Subjects: 
Inclusion criteria: All individuals diagnosed with Atrial Fibrillation and choosing to undergo a rhythm 
control strategy at Robert Packer Hospital with a BMI ≥ 27 will be eligible for the study. All subjects 
must be able to understand and willing to sign a written informed consent document.   
  
Exclusion criteria: Individuals who are already taking metformin or other antidiabetic medications 
including insulin, have a diagnosis of diabetes, have a known allergy or FDA-labeled contraindication to 
taking metformin, eGFR below 30 mL/min per 1.73 m2 or other clinical diagnosis of advanced renal 
disease,, have acute or chronic metabolic acidosis (serum bicarbonate <22 mEq/L), have a history of 
significant alcohol use (>2 drinks/day on average), have a history of hepatic dysfunction (serum bilirubin 
1.5X greater than the upper limit of normal), have a history of New York Heart Association (NYHA) 
Class III or IV heart failure, or are pregnant will be excluded from the trial. 
  
Treatment of Subjects: 
At baseline all study patients will be assessed for:  
 
Age, Gender, Weight, BMI, Tobacco Use, Hypertension, Hemoglobin A1c, Hyperlipidemia, serum 
CRP, eGFR, liver function tests (AST, ALT, ALP, bilirubin, albumin, INR), History of Coronary 
Artery Disease by MI, PCI, or CABG, History of Valvular Disease, History of Sleep Apnea, Type of 
AF and duration, Number of Antiarrhythmic Medications  (not including beta-blockers or calcium 
channel blockers). 
 
 In addition, patients will fill out a survey to determine their Atrial Fibrillation Severity Score (AFSS) 
– a validated tool to assess the symptomatic burden of AF - and will receive education on dietary 
changes and exercise. 
 
Subjects will be randomized to receive either Metformin (500 mg tablet) or into the control group.  
Subjects will be instructed to take one tablet twice a day with meals. Over a 3 week period, the dosage 
will be increased to 2000 mg daily (given in a divided dose of 1000 mg twice a day) as tolerated by the 
patient.   
 
Patients will be followed up in regular intervals after the initial attempt at rhythm control. The minimum 
follow up interval is every three months. More frequent follow up may be scheduled as deemed necessary 
by the treating physician.  
 
At the time of the first attempt at rhythm control, at the 3 month follow up, and at the 6 month follow up 
all study patients will be assessed again for:  
Weight, BMI, Hemoglobin A1c, serum CRP, eGFR, liver function tests (AST, ALT, ALP, bilirubin, 
albumin, INR), number of antiarrhythmic agents, presence of AF by EKG, Atrial Fibrillation Severity 
Score, occurrence of adverse events. 
 

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Study Drug Compliance: 
Study drug dispensed to the subjects will be tracked. Subjects will return empty study drug containers and 
unused study drug at those visits when a new supply of study drug is to be received. Study drug 
accountability will be performed at each visit. Subjects should report any unintentional interruption or 
missed doses of 7 consecutive days or more to the study-site personnel at each visit. It is understood that 
subjects may occasionally miss a dose or that a subject may be placed on temporary discontinuation. 
 
Outcomes and Assessment of Efficacy:  
The primary outcome by intention to treat analysis will be maintenance of sinus rhythm by chart review, 
EKG, and Atrial Fibrillation Severity Score at 3 and 6 months after the initial attempt at rhythm control.  
 
Secondary outcomes will include hospitalization related to arrhythmic events or medication side effects, 
number of antiarrhythmic medications, number of repeat ablations, BMI, Hemoglobin A1c, and number 
of thromboembolic events.  
 
Pre-specified subgroup comparisons will include comparing patients randomized to metformin who have 
a 5% reduction in weight at 6 months to all control patients who achieve a 5% reduction in weight, and to 
all control patients. 
 
Assessment of Safety: 
A Medical Monitor will be utilized to provide general oversight and safety considerations for this study. 
The Medical Monitor will provide advice to the Sponsor-Investigator regarding actions the committee 
deems necessary for the continuing protection of subjects enrolled in this study. The Medical Monitor will 
be charged with assessing such actions in light of an acceptable risk/benefit profile for metformin. The 
Medical Monitor will act in an advisory capacity to the Sponsor-Investigator and will monitor subject 
safety data for the study. 
 
All patients included in the study will have monitoring of renal function, hepatic function, and serum 
lactic acid at baseline, at the time of ablation or initiation of rhythm control, and at 3-month and 6-month 
follow ups. This data will be reviewed by an investigator who is not involved in the outcome analysis. 
This investigator will be a mid-level who will be assigned to check the routine labs. The parameters for 
immediate reporting to one of the study coordinators are the following- creatinine greater than or equal to 
1.5 in males or 1.4 in females, elevated lactic acid, or serum bilirubin >1.5x the upper limit of normal. 
Exclusion criteria will also be reviewed at each follow up, and if at any point a patient meets the exclusion 
criteria for the study or has an unexpected adverse event they will be withdrawn from the study.   
 
Routine reports will be provided to the Medical Monitor every 2 months and will include rates of 
disenrollment, reason for disenrollment, unexpected adverse events, and mortalities. If a statistically 
significant harm is detected in the analysis of the safety data collected at 2 month intervals the protocol 
will be terminated. 
 
Adverse events will be solicited at routine follow-up with a designee and are defined as follows: .  
Lactic Acidosis – lactic acid >2.1 mmol/L as measured at either routine follow up or if measured 
during a hospitalization for any reason 
 
Thromboembolic event – any stroke, mesenteric ischemia, limb ischemia, or other event  
determined to be of an embolic etiology secondary to atrial fibrillation 
Vitamin B12 levels and any change from baseline at the 3 and 6 month timepoints will be 
measured and submitted.  
 

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Adverse events will be reviewed every  2-months and a statistical analysis will be done. If the analysis 
finds that any of these adverse events have occurred more frequently in either group in a statistically 
significant manner, the trial will be stopped. 
 
Potential Risks:   
Per the Glucophage (metformin) package insert, metformin does not cause hypoglycemia in individuals 
with diabetes mellitus or normal subjects except in certain circumstances excluded by the study’s 
exclusion criteria.25  
  Metformin does have a warning for the risk of lactic acidosis. Per the insert:   
  
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very 
low (approximately 0.03 cases/1000 patientyears, with approximately 0.015 fatal cases/1000 
patientyears). In more than 20,000 patient-years exposure to metformin in clinical trials, there 
were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients 
with significant renal insufficiency, including both intrinsic renal disease and renal hypo 
perfusion, often in the setting of multiple concomitant medical/surgical problems and multiple 
concomitant medications.25  
In a more recent review of pooled data from 347 trials and cohort studies an estimated risk of 4.3 cases of 
lactic acidosis in 100,000 patient years was calculated and this risk was equivalent with other anti-
hyperglycemic agents.26  The ultimate conclusion of this investigation was “There is no evidence to date 
that metformin therapy is associated with an increased risk of lactic acidosis or with increased levels of 
lactate compared with other antihyperglycemic treatments if the drugs are prescribed under study 
conditions, taking into account contraindications”.26  
  
Other known adverse reactions to metformin therapy include gastrointestinal side effects which include 
flatulence, diarrhea, nausea and vomiting, and abdominal discomfort. These symptoms are dose 
dependent and can be relieved by dose reduction. Approximately 50% of all patients can tolerate a 
maximal dose of metformin but a small minority of around 5% cannot tolerate any dose of metformin.  
27  
Potential Benefits:  
The potential benefits to patients who agree to enroll in this study include the potential benefits of 
metformin therapy and the benefits of more frequent follow up. In addition the previously discussed 
evidence to show weight loss, metformin therapy has been demonstrated to have several potential 
beneficial effects including a decrease in progression from prediabetes to diabetes and improved cancer 
mortality compared to patients taking other diabetic therapies and non-diabetic individuals,28,29   
 
Statistics: 
We expect a 30% recurrence of AF after patients undergo ablation. After ablation, we expect the 
recurrence of AF to be 30% less in the intervention group of patients on metformin than the control group. 
 
Using an 80% power at a 95% confidence interval, the sample size of the control group (ablation only) 
and the intervention group (ablation plus metformin) will be 400 each for a two tailed study, accounting 
for up to a 3% attrition rate in each group. The total sample size of this study will be 800.   It is estimated 
to take five years to accrue subjects. 
 

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Statistical methods employed to analyze outcomes will be a Pearson’s X2 test for categorical variables. 
Analysis of Variance will be used for continuous variables. All tests are two-sided and P <.05 will be used 
to indicate a statistically significant difference.  
 
Direct Access to Source Data/Documents: 
The investigator will permit trial-related monitoring, audits, IRB review and regulatory inspection(s) by 
providing direct access to source data/documents. 
 
Record Retention: 
In compliance with the ICH/GCP guidelines, the investigator will maintain all source documents that 
support the data collected from each subject, as well as all study documents. 
 
Essential documents will be retained until at least 2 years after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an ICH region 
or until at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  
 
Ethics: 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board (IRB) approval prior to initiation 
of the study. 
 
Procedures to Obtain and Record Informed Consent:  
All patients will be provided with a written consent document which will contain the purpose of the study, 
the procedures of the study, and the potential risks and benefits to participating in the study in language 
that is accessible to the lay public. This document will also clearly state that participation in the study is 
voluntary and the decision to participate will not affect other aspects of their care. The document will also 
clearly state that a patient may withdraw from the study at any time they choose. Each patient will meet 
with an investigator to assess the patient’s understanding of the risks and benefits before providing verbal 
and written informed consent. Patients who are medically or cognitively incapacitated and cannot provide 
their own consent will be excluded from the study.   
 
Subject Compensation:  
Subjects will not receive any form of monetary compensation for participation in this study.   
 
Procedures to Maintain Confidentiality:   
The only identifying information that will be retained after the follow up period is the patient’s medical 
record number. All data will be stored in password encrypted files. Any breaches of confidentiality will 
be reported to the IRB and Corporate Compliance Department.  
 
Registration: The clinical trial will be registered with ClinicalTrials.gov an International Committee of  
Medical Journal Editors approved public registry.  
   
References:  
1. 
 Fuster V, Rydén L, Cannom D ,Crijns H, Curtis A, Ellenbogen K, Halperin J, Le Heuzey JY, Kay  

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CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, 
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