(MATE) Metformin and Aging Trial in the Elderly: A Pilot and Feasibility Study
Phase: PHASE2
Conditions: Aging, Inflammation, Frailty
Sponsor: Mayo Clinic

 
 
(MATE) Metformin and Aging 
Trial in the Elderly: A Pilot and 
Feasibility Study 
 
 NCT03451006 
 
 
10/5/2020 

 
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(MATE) Metformin and Aging Trial in the Elderly: A Pilot and Feasibility Study 
 
 
Abstract. Metformin exerts its effect on health span as a calorie restriction-mimetic through activation 
of AMP-activated protein kinase. This drug is safe, inhibits cellular senescence, and prolongs life in 
mammals. We hypothesize that chronic metformin administration through augmentation of cellular 
regeneration and inhibition of senescence improves physical functioning of older adults. In this pilot, 
feasibility study, we aim to administer metformin up to 2 gm or placebo in a 1:1 randomized fashion 
for one year to 12 frail adults, ≥ 60 years with coronary artery disease and assess their physical 
function by frailty measures . Among patients with improved physical function throughput profiling of 
tissue and serological samples will be made to establish a molecular map of the impact of metformin. 
The effect of metformin on several senescent markers (IL-6, MCP-1, MMP-3/9/12, PAI-1/2, and 
activin A) will be tested as well. 
 
Version: 4 
 
Date:  October 5, 2020 
 
 
Principal Investigator: Mandeep Singh, MD, MPH 
 

 
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A. Rationale: Heart disease is the number one cause of death in the United States and 
disproportionately affects older adults, underscoring the need to examine determinants of 
survivorship.1-3 Recognizing this gap, ACC/AHA guidelines lay emphasis to assess frailty, a key 
construct prevalent in elderly and known to impact their prognosis.1, 2,4, 5 Older persons are commonly 
frail, and their health span is truncated by illnesses during which physiological declines together with 
accumulation of additional deficits results in multimorbidity and functional dependence.6-8 High 
incidence of functional decline in patients with coronary artery disease (CAD) 9, 10 makes 
pharmacologic manipulation, an attractive strategy to improve frailty and reduce adverse 
cardiovascular outcomes. Metformin exerts its effect on health span as a calorie restriction-mimetic 
through inhibition of mitochondrial complex 1 and activation of AMP-activated protein kinase.14 This 
drug is safe and has been shown to prolong life in mammals.15 Metformin by reducing effects of 
cellular senescence may improve the functioning of older adults.   
 
In CAD, cellular senescence and inflammation affect organ dysfunction through interference with 
tissue homeostasis and regeneration.16-18 The deleterious effect of senescence includes pro-
inflammatory senescence-associated secretory phenotype (SASP).19 Normal biological function 
through alteration in cellular homeostasis may be achieved by metformin. The phenotypic 
manifestations of these changes are incompletely characterized as it is yet unknown whether cell-
intrinsic regenerative mechanisms can be translated into clinical improvement in physical 
performance and whether it’s chronic administration is safe in older adults. These major gaps in 
knowledge hinder utilization of metformin as an agent to promote cellular regeneration and to reduce 
the impact of cellular senescence. 
 
Targeting frail individuals with high levels of inflammation and SASP factors would necessitate 
identification of predictors of improvement with metformin in tissue inflammation and function. A 
clinomics approach implementing simultaneous assessment of clinical impact coupled with OMICs-
based serological profiling would provide enhanced understanding of the local and systemic impact 
mediated by metformin. Through correlation of molecular profiles with phenotypic expression changes, 
as proposed herein, we will enhance our understanding of the regenerative impact of metformin and 
the basis for clinical improvement in the setting of senescence.  
 
B. Hypothesis: Chronic metformin administration through augmentation of cellular regeneration and 
reduction of senescence will improve frailty and physical functioning.  
C. Innovation: This would be first-in-human pilot safety and feasibility study. There are no studies 
that have investigated the anti-aging potential of metformin. 
 
D. Significance: 1. If proven, metformin will be given to improve physical functioning patients with 
CAD. Larger phase 3 studies would be needed. 2. This will enhance the reputation of Mayo Clinic, 
attract unique patients, and advance our knowledge about cardiovascular disease. 3. Increase in 
AMPK activity by metformin mimics calorie restriction by upregulating macroautophagy, mitochondrial 
biogenesis, inhibiting mTOR-1 allows cells to be functionally fit.14, 20, 21 TOR complex 1 can be 
successfully inhibited by metformin to slow senescence and improve human health.21 Metformin also 
inhibits cellular senescence, a key mammalian longevity pathway.22-24 Metformin extends lifespan in 
nematodes and mammals.25-27 It is safe and prevents progression from impaired glucose tolerance to 
clinical diabetes.28 Metformin among diabetics reduces risk of cardiovascular disease further 
supporting its role in attenuating age-related chronic diseases.29-36 Role of metformin as a 
pharmaceutical intervention to prevent aging is not derived from prospective studies.37 Cellular 
senescence arrests cells at risk for malignant transformation19, however, the harmful effects may 

 
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manifest through their proinflammatory SASP.38 The role of metformin in modifying SASP is less well 
known, it is known to reduce senescence through prevention of translocation of NF-B.23  
 
E. Brief Synopsis of Methods: 12 frail patients ≥60 years with CAD, will be randomized to 
metformin (up to 2.0 gm) or placebo for 1-year to note improvement in frailty. Molecular map through 
high throughput serological profiling and assessment of SASP will be done of responders and 
nonresponders to metformin. An IND exemption is being requested for the use of metformin. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Visit ( CRTU) 
(completed on same day as Frailty Screening) 
 
• 
Blood testing: CBC without differential, BUN, serum albumin, creatinine, AST, ALT, bilirubin 
(total and direct), lipid panel 
• 
Blood sample collection for biomarkers 
• 
Grip strength 
• 
Katz Index of Independence in ADL 
• 
1:1 Randomization to Metformin Group or Placebo Group 
• 
Study drug / placebo dispensation (100 day supply) 
• 
Stool sample & FFQ (optional sub-study) 
3 Month Visit (CRTU) 
• 
Blood testing: CBC without differential, serum albumin, BUN, creatinine, AST, ALT, Bilirubin 
(total and direct), lipid panel 
• 
Short physical performance battery (SPPB), grip strength  
• 
Blood sample collection for biomarkers  
• 
Mini-Mental State Examination (MMSE) 
• 
Katz Index of Independence in ADL 
• 
Study drug / placebo dispensation (100 day supply) 
• 
Stool sample & FFQ (optional sub-study) 
12 Month Visit (CRTU) 
• 
Blood testing: CBC without differential, serum albumin, BUN, Creatinine, AST, ALT, 
Bilirubin (total and direct), lipid panel 
• 
Short physical performance battery (SPPB), grip strength  
• 
Blood sample collection for biomarkers  
• 
Mini-Mental State Examination (MMSE) 
• 
Katz Index of Independence in ADL 
• 
Stool sample & FFQ (optional sub-study) 
Study drug / placebo (100 day supply) mailed out  
at 6 months and 9 months 
Frailty Criteria met? 
Screening For Frailty (CRTU) 
 
• 
Informed consent 
• 
Short physical performance battery (SPPB) < 9 and Mini-Mental State Examination (MMSE) 
yes 
no 
Proceed to baseline visit 
Frailty screen failure – no 
further information collected

 
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F. Preliminary data to support feasibility: In a prospective cohort study, patients ≥ 65 years who 
underwent PCI were assessed for frailty (Fried criteria), comorbidity (Charlson index), and quality of 
life [SF-36].7 Of the 628 patients discharged, 78 died. Following adjustment, frailty was associated 
with long-term mortality. In a recent pilot study39, oral rapamycin (0.5, 1, 2.0 mg) was given for 12 
weeks to 13 non-frail patients who underwent PCI. Plasma and adipose tissue markers of 
senescence were favorably modified by rapamycin [plasma IL-6 decreased from 4.4 to 2.6 pg/ml; 
adipose tissue mRNA expression of p16 (129 vs. 169), and senescence-associated beta 
galactosidase activity decreased (2.2% vs. 3.6%). Moderate correlation between some senescence 
markers and physical functioning was also demonstrated.  
 
Safety of metformin in nondiabetics: The safety of metformin in patients without diabetes is well 
demonstrated in patients with diverse indications. In the Glycometabolic Intervention as Adjunct to 
Primary Coronary Intervention in ST-segment-elevation Myocardial Infarction (GIPS-III) randomized 
trial on 380 patients without diabetes mellitus, who received 1 gm of metformin for 4 months, no 
cases of lactic acidosis were observed.40 Importantly, the levels of creatinine, glucose, and HBA1C 
levels did not differ between the groups taking metformin or placebo underscoring the safety of the 
drug. Higher gastrointestinal side effects, which were self-limiting and did not require discontinuation 
of metformin were observed in patients with erectile dysfunction who also had insulin resistance as 
compared to placebo (61.5% vs. 7.7%, P=0.03).41 Similar results (higher gastrointestinal side effects) 
were seen with metformin in women with polycystic ovary syndrome (OR 4.49, 95% CI 1.88-10.72)42 
or as an addition to chemotherapy in patients with advanced pancreatic cancer43 or when given to 
non-diabetic patients with coronary heart disease (CAMERA study)44 or with metformin pretreatment 
in patients undergoing coronary artery bypass surgery.45 
 
G. Study design: This will be a pilot, feasibility study. Twelve subjects ≥ 60 years with  CAD, who are 
determined to be frail will be randomized to receive up to 2.0 gm of oral metformin or placebo for 12 
months.  
 
Study visits: Assessments will be done at three predefined time intervals: baseline, 3 months, and at 
1 year. During these visits, workup will include complete blood count, BUN, creatinine, AST, ALT, 
bilirubin total, bilirubin direct, serum albumin, and fasting lipid panel, frailty assessment with short 
physical performance battery (SPPB) and grip strength, Mini-Mental State Examination (MMSE), Katz 
Index of Independence in ADL, stool sample and Food Frequency Questionnaire (optional sub-study), 
serum markers of senescence and OMICs (see Schedule of Events). All visits will have a +/- two 
week window for assessment. Measurement of frailty will be done by the study coordinator. A brief 
self-report regarding recent use of antibiotics, laxatives, and colonoscopy colon prep agents will be 
done at each visit. At each visit, subjects will be asked about side effects. Subjects with serious side 
effects from the medications will be withdrawn from the study, Appendix 1.  
 
Recruitment of subjects: Clinics (CAD and Cardiac Education) with high number of patients with 
CAD will be screened daily for potential participants. We will also screen daily the inpatient census for 
patients who undergo percutaneous coronary interventions. In addition, we have developed 
computerized algorithms using inclusion/exclusion criteria (listed below), and diagnostic codes. These 
algorithms will be applied to the EMR and to the Common Data Model (CDM) established and 
maintained under IRB 19-005480 (PI: VL Roger, Co-I on this study), to identify potentially eligible 
subjects. The eligibility also includes absence of known diabetes mellitus and presence of significant 
renal dysfunction (GFR <45ml/min). If person meets all these criteria (age ≥60 years, absence of 
diabetes mellitus, and significant chronic renal failure [GFR<45ml/min]), the eligible participants will 
be contacted via an e-mail/letter.  We will send recruitment letters to those who have a high likelihood 
of being eligible asking if they are interested in participating in the study.  If the patient is interested in 

 
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participating, we will schedule a phone visit with prescreening questions to determine their likelihood 
of being frail.  If they are deemed likely to be frail, then we will have them come for a screening and 
baseline visit.   
 
If the patient agrees to participate in the study, the written informed consent will be obtained during 
the screening and baseline visit before any tests are performed. The consent process will occur in a 
private setting on the Mayo Clinic campus. The study team member will review the entire consent 
with the potential participant and answer any questions they may have about the research proposal. 
The potential participant will be provided as much time as needed to decide whether they want to 
participate or not. All potential participants will be assured that their clinical care will not be affected in 
any way if they choose not to participate. 
 
Definitions: Coronary artery disease: Any patient with a diagnosis of CAD will be included. CAD will 
be defined as patients with history of angina, positive stress test, prior PCI or coronary artery bypass 
surgery or patients with significant coronary artery disease detected on CT scan. . Patients with 
known DM or new-onset DM will be excluded. Patients presenting with acute coronary syndrome or 
patients participating in cardiac rehabilitation will be eligible.   
 
Inclusion Criteria:  
• Age ≥ 60 years 
• CAD 
• Frailty as determined by the short physical performance battery 
• Able to return for follow-up 
• Written informed consent 
 
Exclusion criteria: 
• Pre-existing or new-onset diabetes 
• Any active malignancy, hematological disorder, post organ transplant, immunocompromised 
• Cancer requiring treatment in the past 3 years (other than non-melanoma skin cancer) 
• Dementia [mini mental state examination (MMSE <20)] 
• Prior stroke with disability 
• Severe Parkinson’s 
• Hepatic insufficiency and/or chronic liver disease (cirrhosis) 
• Chronic kidney disease (GFR < 45 mL/min) 
• Taking metformin for any indication 
• Acute alcohol intoxication 
• Known hypersensitivity to metformin hydrochloride 
• Acute/chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma 
 
Measurement of frailty: In prescreening patients via phone, we will ask 6 questions regarding ADLs 
and self-care to determine who will have a high likelihood of being frail. At the screening visit we will 
use the short physical performance battery (SPPB; Appendix 2) for identification of eligible 
participants. We will also measure frailty using the SPPB and grip strength at baseline, 3 months, and 
at the end of the study. Single-item frailty measures, such as gait speed, grip strength and repeated 
chair stands (if the participant is able to do), have shown important prognostic value in patients with 
CAD and will be recorded. Factors that potentially influence frailty (regular exercise regimen, vitamin 
D supplementation, high protein or calorie-restricted diet, or polypharmacy) will be recorded at each 
follow-up visit.  
 

 
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Administration of Metformin The gastrointestinal intolerance (diarrhea, nausea, bloating etc.) is 
associated with higher dose initiation and rapid dose escalation.47 The pharmacist under the guidance 
of an endocrinologist will start metformin at a lower dose (500 mg twice a day with meals) and 
increase the dose at one-week interval to a maximum tolerable daily dose up to 1.0 gm twice a day, 
depending upon patient’s tolerance.48 Since metformin does not stimulate insulin secretion, 
hypoglycemia is rarely observed.49 Randomization to drug or placebo will be done by the statistician 
to ensure blinding. Administration and monitoring of metformin/placebo will be done by the study 
coordinator under the supervision of an endocrinologist, who will not be involved in the routine care or 
follow-up of these patients. The drug will be stopped during hospitalization for repeat angiography, or 
any acute condition that can adversely affect renal function or can cause lactic acidosis (infection, 
dehydration etc.). The study medication (placebo or metformin) will be restarted following hospital 
discharge according to the current FDA recommendations. Renal function will be monitored as a part 
of their clinical care on follow-up. The drug will be discontinued in patients reporting significant 
adverse effects. 
 
Plan for alerting the staff for side effects 
 
The most common side effects are gastrointestinal. To reduce the incidence of these side 
effects, the dose of metformin will be slowly increased and will be given with meals. In the event of 
intolerable gastrointestinal side effects, the participant will contact the study coordinator via phone call 
(provided at the time of consent and enrollment). The study coordinator will inform the Principal 
Investigator and will determine whether a dose reduction is needed (which will be done over the 
phone) or the participant needs an additional visit. The study coordinator will make a follow-up phone 
call in one week to inquire whether the side effects have improved/resolved. If they have, the 
participant will continue with the protocol. If the participant needs to come in due to severity of side 
effects or the side effects don't resolve, the PI will see the participant and in consultation with the 
endocrinologist will determine whether to continue the drug, lower the dose, or stop the drug. If the 
drug is stopped, the final measurements will be done at that time. 
 
Blinding: To ensure blinding, we will take the following steps. The investigators will be blinded to the 
treatment assignment. The pill count, change in the metformin dose, adverse effect reporting, data 
entry in the case report form (CRF) will be done by the main study coordinator. Measurement of frailty, 
MMSE, Katz ADL is done by a second study coordinator who will be unaware of the drug assignment. 
The pharmacist will not be involved in the routine care or follow-up of these patients. If the 
discontinuation of study drug is due to serious adverse effects, the principal investigator will contact 
the primary care provider and further management will be instituted. 
 
Molecular markers: 50 mL of whole blood will be collected for omics assessment. EDTA tubes will 
be used by the CRTU staff to collect serological samples. The samples will be sent via pneumatic 
tube shuttle to the Hilton building for pick up by the Behfar study team. Samples will be spun down, 
processed and/or stored for omics analysis. Study samples will be logged into the RLIMS system for 
sample management. Five randomly selected serological samples will undergo ELISA-based array 
evaluation to simultaneously quantify 1200 unique cytokines and growth factors. For non-stochastic 
evaluation, column-based immunodepletion will be utilized to eliminate albumin from five randomly 
selected samples prior to 2D-Gel separation and MS spectrometry-based deconvolution to establish 
the serum proteome. Serum samples will also undergo density filtration followed by rapid 
lyophilization or density concentration for isolation of the exosomal fraction. Purified serum exosomes 
will be enriched for small RNAs and subjected to miRNomics analysis. Data sets collected from this 
cohort will be cross-referenced with clinical frailty following chronic metformin treatment to document 
regenerative impact at the molecular level. This clinomics-based profiling will provide biomarker 

 
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readout to yield a systems-biology map of the mechanistic basis for regenerative benefit in those 
responsive to metformin therapy. The remaining samples will be stored for future use.  
 
Serum SASP markers: will be measured at baseline, 3 months, and 12 months on all subjects. 
Serological markers of senescence will include [interlukin-6 (IL-6), matrix metalloproteinase (MMP) 3, 
9, and 12, PAI-1 and -2, activin A, and monocyte chemotactic protein (MCP)].  
 
Optional Microbiome Sub- Study protocol: The optional stool samples will be labeled with an 
ARLIMS tracking number and will be frozen at -80C. At study completion, samples will undergo DNA 
isolation and subjected to Ribosomal DNA evaluation to delineate and speciate the microbiological 
content of the stool (Microbiome). For those who agree, a patient stool sample kit will be mailed to 
each patient prior to their outpatient appointment and will be collected in a fecal tube collection kit 
prior to their outpatient visit at baseline, 3 month and 12 months. The patient will bring the kit at time 
of appointment and the sample will be stored in a secured research facility for microbiome analysis. 
The Mayo Clinic Clinical Research Trials Unit will assist in stool sample pick-up and short-term -80oC 
storage prior to study staff retrieval. 
 
Food Frequency Questionnaire: An electronic VioFFQ food frequency questionnaire will be 
administered to those who consent to optional microbiome sub-study, from Viocare Technologies, Inc. 
to determine dietary patterns over the last 90 days; completed, de-identified questionnaires will be 
analyzed by a Mayo Clinic research dietician and returned to study staff.  
 
Self-Report: A brief self-report regarding recent use of antibiotics, laxatives, and colonoscopy colon 
prep agents will be distributed to consenting patients and considered as metadata. These responses 
may be verified by study staff in a chart review where possible. 
 
 
Schedule of Events 
Tests 
Screening 
Visit 
Baseline 
Visit  
3 Month Visit 
(at conclusion 
of CR, ± 2 
weeks) 
12 Month 
Visit 
(± 2 
weeks) 
Informed Consent 
X 
 
 
 
Randomization 
 
X 
 
 
CBC (without differential) 
 
X 
X 
X 
Serum Albumin 
 
X 
X 
X 
Blood Urea Nitrogen (BUN) 
 
X 
X 
X 
Creatinine (serum) 
 
X 
X 
X 
AST 
 
X 
X 
X 
ALT 
 
X 
X 
X 
Bilirubin (total) 
 
X 
X 
X 
Bilirubin (direct) 
 
X 
X 
X 
Fasting lipid panel  
 
X 
X 
X 
Blood sample collection for 
molecular & SASP markers 
 
X 
X 
X 
Frailty assessment  
X 
X 
X 
X 
Mini-Mental State Examination 
(MMSE) 
X 
 
X 
X 

 
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Katz Index of Independence in ADL 
 
X 
X 
X 
Stool sample (optional sub-study) 
 
X 
X 
X 
Food Frequency Questionnaire 
(optional sub-study) 
 
X 
X 
X 
Self-report of antibiotics, laxatives, 
and colonoscopy history 
 
X 
X 
X 
 
H. Statistical analyses and power considerations: This is a pilot study and will not be powered to 
detect specific effect sizes. Importantly, measures of variation from this study will be used to power 
future studies. 
 
I. Human study issues:  
Human Subjects Safety: An independent, internal data and safety monitoring board (DSMB) will 
oversee the progress and safety of the trial and will advise the investigators whether to continue, 
modify, or terminate the trial. Potential risks to participants may include side effects from metformin. 
Protection of patient’s identity will follow the Department guidelines for handling and storage of 
research data. Standardized systems to ensure patient confidentiality will be maintained.  
 
Medication safety will be ensured by not giving metformin to anyone who has history of 
hypersensitivity to metformin or who have moderate-to-severe renal impairment 
(GFR<45mL/min/1.73m2. Participants on metformin will discontinue the drug to prevent lactic 
acidosis if they will have a radiologic study with contrast, surgery, excessive alcohol intake, or any 
other precipitating factors. The only other serious adverse effect of hepatitis will be periodically 
monitored by blood tests, including serum bilirubin, ALT and AST.  
 
Early withdrawal of Subjects: Participants with serious adverse effects from the medications will 
discontinue medication use, but will continue with the study visits, unless they wish to completely 
withdraw from the study. We will make arrangements for the participant to be seen by their primary 
MD for follow-up. At any other time, patients will contact the main study coordinator, if they develop 
and want to report any side effects. We will also discontinue medication use if the participants fail to 
follow the protocol or are unwilling to continue the prescribed medication.  
Patients who discontinue the drug will come for their final check-up and will include frailty assessment, 
and blood draw for biomarkers. We would use intention-to-treat analyses and would not add any 
other subjects. The subjects who discontinue the study drug will be followed-up by a phone call at 
one month. If the discontinuation is due to serious adverse effect, the patient will be asked to contact 
the primary care provider and further management will be instituted.  
Stopping Rules: Following rules will be applied to stop the study. 
Death of any participant. Following death of any participant, we will stop the study and analyze the 
cause of death. We will inform IRB and DSMB as well. If the cause of death is unrelated to the drug, 
then after informing IRB with the permission of DSMB, the study will be restarted. If death is directly 
related to the drug, the study will be stopped. 
 
In case of nonfatal serious side effects observed in one patient, the drug will be stopped in that 
patient and trial will be stopped as well.

 
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27. 
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Greene ND and Gems D. Metformin retards aging in C. elegans by altering microbial folate and methionine 
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Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England journal 
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Holman RR, Paul SK, Bethel MA, Matthews DR and Neil HA. 10-year follow-up of intensive glucose 
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Johnson JA, Simpson SH, Toth EL and Majumdar SR. Reduced cardiovascular morbidity and mortality 
associated with metformin use in subjects with Type 2 diabetes. Diabet Med. 2005;22:497-502. 
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Whittington HJ, Hall AR, McLaughlin CP, Hausenloy DJ, Yellon DM and Mocanu MM. Chronic 
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Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO and Bilo HJ. Metformin associated 
with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33:322-6. 
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Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH and Huang YC. Type 2 diabetes increases and 
metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative 
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low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620-5. 
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Harst P, van Veldhuisen DJ and Investigators G-I. Effect of metformin on left ventricular function after acute 
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Prediabetes. Cell Rep. 2016;15:1394-400. 
 
Appendices: 
Appendix 1 
Contraindications, warnings, precautions, adverse reactions and overdosage of metformin. 
(Sources: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020357s031,021202s016lbl.pdf  
and 
http://www.fda.gov/downloads/drugs/drugsafety/ucm494140.pdf) 
 
CONTRAINDICATIONS 
Metformin are contraindicated in patients with:  
1.  Metformin is contraindicated in patients with an eGFR below 30 mL/minute/1.73 m . 
2.  Starting metformin in patients with an eGFR between 30-45 mL/minute/1.73 m is not recommended. 
3. Known hypersensitivity to metformin hydrochloride.  

 
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4. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic 
ketoacidosis should be treated with insulin.  
Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular 
administration of iodinated contrast materials, because use of such products may result in acute alteration of 
renal function.  
 
WARNINGS  
Lactic Acidosis:  
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation 
during treatment with Metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may 
also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and 
whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated 
blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and 
an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin 
plasma levels >5 μg/mL are generally found.  
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low 
(approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). 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 hypoperfusion, often in the setting of multiple concomitant medical/surgical 
problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic 
management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion 
and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of 
renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by 
regular monitoring of renal function in patients taking Metformin and by use of the minimum effective dose of 
Metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal 
function. Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of 
creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to 
developing lactic acidosis. In addition, Metformin should be promptly withheld in the presence of any condition 
associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit 
the ability to clear lactate, Metformin should generally be avoided in patients with clinical or laboratory 
evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or 
chronic, when taking Metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate 

 
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metabolism. In addition, Metformin should be temporarily discontinued prior to any intravascular radiocontrast 
study and for any surgical procedure. 
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, 
myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be 
associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient 
and the patient’s physician must be aware of the possible importance of such symptoms and the patient should 
be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the 
situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and 
even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Metformin, 
gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later 
occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.  
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients 
taking Metformin do not necessarily indicate impending lactic acidosis and may be explainable by other 
mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in 
sample handling. 
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of 
ketoacidosis (ketonuria and ketonemia).  
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis 
who is taking Metformin, the drug should be discontinued immediately and general supportive measures 
promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min 
under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove 
the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.  
PRECAUTIONS  
General  
Macrovascular Outcomes—There have been no clinical studies establishing conclusive evidence of 
macrovascular risk reduction with Metformin or any other anti-diabetic drug.  
Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of 
metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, 
patients with serum creatinine levels above the upper limit of normal for their age should not receive 
Metformin. In patients with advanced age, Metformin should be carefully titrated to establish the minimum 
dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, 
particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Metformin 
should not be titrated to the maximum dose.  

 
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Before initiation of Metformin therapy and at least annually thereafter, renal function should be assessed and 
verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should 
be assessed more frequently and Metformin discontinued if evidence of renal impairment is present.  
Use of concomitant medications that may affect renal function or metformin disposition—Concomitant 
medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with 
the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be 
used with caution.  
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous 
urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular 
contrast materials)—Intravascular contrast studies with iodinated materials can lead to acute alteration of renal 
function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in 
whom any such study is planned, Metformin should be temporarily discontinued at the time of or prior to the 
procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has 
been re-evaluated and found to be normal.  
Hypoxic states—Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute 
myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic 
acidosis and may also cause prerenal azotemia. When such events occur in patients on Metformin therapy, the 
drug should be promptly discontinued.  
Surgical procedures—Metformin therapy should be temporarily suspended for any surgical procedure (except 
minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the 
patient’s oral intake has resumed and renal function has been evaluated as normal.  
Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, 
therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Metformin.  
Impaired hepatic function—Since impaired hepatic function has been associated with some cases of lactic 
acidosis, Metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic 
disease.  
Vitamin B12 levels—In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal 
levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in 
approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-
intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible 
with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters 
on an annual basis is advised in patients on Metformin and any apparent abnormalities should be appropriately 
investigated and managed.  

 
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Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be 
predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 
measurements at two- to three-year intervals may be useful.  
Change in clinical status of patients with previously controlled type 2 diabetes—A patient with type 2 diabetes 
previously well controlled on Metformin who develops laboratory abnormalities or clinical illness (especially 
vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. 
Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, 
pyruvate, and metformin levels. If acidosis of either form occurs, Metformin must be stopped immediately and 
other appropriate corrective measures initiated.  
Hypoglycemia—Hypoglycemia does not occur in patients receiving Metformin alone under usual circumstances 
of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric 
supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and 
insulin) or ethanol.  
Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol 
intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in 
the elderly, and in people who are taking beta-adrenergic blocking drugs.  
Loss of control of blood glucose—When a patient stabilized on any diabetic regimen is exposed to stress such as 
fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be 
necessary to withhold Metformin and temporarily administer insulin. Metformin may be reinstituted after the 
acute episode is resolved.  
The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many 
patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or 
to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in 
which the drug is ineffective during initial therapy. Should secondary failure occur with either Metformin or 
sulfonylurea monotherapy, combined therapy with Metformin and sulfonylurea may result in a response. 
Should secondary failure occur with combined GLUCOPHAGE/sulfonylurea therapy or metformin 
XR/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin 
therapy. 
 
 
 
 

 
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ADVERSE REACTIONS  
 
 
 
 
 
 
 
 
 
 
 
 
*Reactions that were more common in metformin than placebo treated patients. 
 
In a US double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients 
received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions 
reported in greater than 5% of the metformin patients, and that were more common in metformin- than placebo-
treated patients, are listed in Table 1. 
Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Additionally, the 
following adverse reactions were reported in 1.0 - 5.0% of metformin patients and were more commonly 
reported with metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail 
disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. 
OVERDOSAGE 
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. 
Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin 
hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin 
overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic 
conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom 
metformin overdosage is suspected. 
Table 11: Most Common Adverse Reactions (>5.0 Percent) in a Placebo- Controlled Clinical 
Study of metformin Monotherapy* 
Adverse Reaction 
metformin 
Monotherapy 
(n=141) 
Placebo 
(n=145) 
% of Patients 
Diarrhea 
53.2 
11.7 
Nausea/Vomiting 
25.5 
8.3 
Flatulence 
12.1 
5.5 
Asthenia 
9.2 
5.5 
Indigestion 
7.1 
4.1 
Abdominal Discomfort 
6.4 
4.8 
Headache 
5.7 
4.8 

 
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Appendix 2 
 
Phone Prescreening Questions to Identify Patients Likely to Be Frail 
 
1. Can you climb two flights of stairs without stopping to rest? 
2. Do you have difficulty completing any of the following activities on your own? 
a. Preparing meals 
b. Feeding yourself 
c. Dressing 
d. Using the toilet 
e. Housekeeping 
f. Climbing stairs 
g. Bathing 
h. Walking 
i. Using transportation 
j. Getting in and out of bed 
k. Managing medications 
3. Which of the following describes your living environment? 
a. House; apartment; assisted living; nursing home; other 
4. Do you depend on any assistive devices such as a cane, wheelchair, braces, walker, or 
assistance from other people to perform activities important to you in your daily life? 
5. Do you wear dentures? 
6. Do you have hearing aids? 
 
If the patient answers no to question 1 or yes to any items under question 2, or questions 4-6, then 
that is a marker of possible frailty. We will invite all patients for the baseline screening visit, if there 
are 3 or more positive answers that suggest markers of frailty. 
 
Short Physical Performance Battery  
1. Repeated Chair Stands  
 
Instructions: Do you think it is safe for you to try and stand up from a chair five times without using 
your arms? Please stand up straight as quickly as you can five times, without stopping in between. 
After standing up each time, sit down and then stand up again. Keep your arms folded across your 
chest. Please watch while I demonstrate. I’ll be timing you with a stopwatch. Are you ready? Begin  
 
Grading: Begin stop watch when subject begins to stand up. Count aloud each time subject arises. 
Stop the stopwatch when subject has straightened up completely for the fifth time. Also stop if the 
subject uses arms, or after 1 minute, if subject has not completed rises, and if concerned about the 
subject’s safety.. Record the number of seconds and the presence of imbalance.. Then complete 
ordinal scoring.  
 
Time: _____sec (if five stands are completed)  
Number of Stands Completed: 1 2 3 4 5  
Chair Stand Ordinal Score: _____  
0 = unable  
1 = > 16.7 sec  
2 = 16.6-13.7 sec  
3 = 13.6-11.2 sec  

 
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4 = < 11.1 sec  
 
2. Balance Testing  
 
Begin with a semitandem stand (heel of one foot placed by the big toe of the other foot). Individuals 
unable to hold this position should try the side-by-side position. Those able to stand in the 
semitandem position should be tested in the full tandem position. Once you have completed time 
measures, complete ordinal scoring.  
 
a. Semitandem Stand  
 
Instructions: Now I want you to try to stand with the side of the heel of one foot touching the big toe 
of the other foot for about 10 seconds. You may put either foot in front, whichever is more comfortable 
for you. Please watch while I demonstrate.  
 
Grading: Stand next to the participant to help him or her into semitandem position. Allow participant 
to hold onto your arms to get balance. Begin timing when participant has the feet in position and lets 
go.  
 
Circle one number  
2. Held for 10 sec  
1. Held for less than 10 sec; number of seconds held _____  
0. Not attempted  
 
b. Side-by-Side stand  
 
Instructions: I want you to try to stand with your feet together, side by side, for about 10 sec. Please 
watch while I demonstrate. You may use your arms, bend your knees, or move your body to maintain 
your balance, but try not to move your feet. Try to hold this position until I tell you to stop.  
 
Grading: Stand next to the participant to help him or her into the side-by-side position. Allow 
participant to hold onto your arms to get balance. Begin timing when participant has feet together and 
let’s go.  
 
Grading  
2. Held of 10 sec  
1. Held for less than 10 sec; number of seconds held_____  
0. Not attempted  
 
c. Tandem Stand  
 
Instructions: Now I want you to try to stand with the heel of one foot in front of and touching the toes 
of the other foot for 10 sec. You may put either foot in front, whichever is more comfortable for you. 
Please watch while I demonstrate.  
 
Grading: Stand next to the participant to help him or her into the side-by-side position. Allow 
participant to hold onto your arms to get balance. Begin timing when participant has feet together and 
let’s go.  
 
Grading  

 
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2. Held of 10 sec  
1. Held for less than 10 sec; number of seconds held_____  
0. Not attempted  
 
Balance Ordinal Score: _____  
0 = side by side 0-9 sec or unable  
1 = side by side 10, <10 sec semitandem 2 = semitandem 10 sec, tandem 0-2 sec  
3 = semitandem 10 sec, tandem 3-9 sec  
4 = tandem 10 sec  
 
3. 8’ Walk (2.44 meters)  
 
Instructions: This is our walking course. If you use a cane or other walking aid when walking outside 
your home, please use it for this test. I want you to walk at your usual pace to the other end of this 
course (a distance of 8’). Walk all the way past the other end of the tape before you stop. I will walk 
with you. Are you ready?  
 
Grading: Press the start button to start the stopwatch as the participant begins walking. Measure the 
time take to walk 8’. Then complete ordinal scoring.  
 
Time: _____ sec  
Gait Ordinal Score: _____  
0 = could not do  
1 = >5.7 sec (<0.43 m/sec)  
2 = 4.1-6.5 sec (0.44-0.60 m/sec)  
3 = 3.2-4.0 (0.61-0.77 m/sec)  
4 = <3.1 sec (>0.78 m/sec)  
 
Summary Ordinal Score: _____  
 
Range: 0 (worst performance) to 12 (best performance). Shown to have predictive validity showing a 
gradient of risk for mortality, nursing home admission, and disability.  
 
Reprinted from Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, Scherr PA, 
Wallace RB. A short physical performance battery assessing lower extremity function: association with 
self-reported disability and prediction of mortality and nursing home admission. J Gerontol Med Sci 
1994; 49(2):M85-M94