4

Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program

Metformin Use in Patients with 

Contraindications or 

Precautions 

September 2016

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420 

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Durham VA Medical Center

Durham, NC 

John W. Williams, Jr., MD, MHSc, Director 

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Investigators:

Principal Investigators: 

Matthew J. Crowley, MD

Clarissa J. Diamantidis, MD

John W. Williams, Jr, MD, MHSc

Co-Investigators: 

Jennifer R. McDuffie, PhD

Blake Cameron, MD

John Stanifer, MD

Clare K. Mock, MD

Andrzej Kosinski, PhD

Xianwei Wang, MD

Shuang Tang, MD, PhD

Research Associates: 

Avishek Nagi, MS

Liz Wing, MA

NOTE: This publication is for internal use of the Department of 

Veterans Affairs and should not be distributed outside the agency.
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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PREFACE 

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and 

policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding 

for four ESP Centers, and each Center has an active University affiliation. Center Directors are 

recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based 

Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA 

Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as 

designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help: 

Develop clinical policies informed by evidence;

Implement effective services to improve patient outcomes and to support VA clinical practice 

guidelines and performance measures; and 

Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence 

syntheses have informed the clinical guidelines of large professional organizations.

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the 

capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program 

development and evaluation, and dissemination efforts. The ESP CC establishes standard operating 

procedures for the production of evidence synthesis reports; facilitates a national topic nomination, 

prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial 

review processes; ensures methodological consistency and quality of products; produces “rapid response 

evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for 

Information Dissemination and Education Resources (CIDER) to develop a national dissemination 

strategy for all ESP products; and interfaces with stakeholders to effectively engage the program. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program 

Manager, at Nicole.Floyd@va.gov.

Recommended citation: Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron B, Stanifer J, Mock CK, 

Kosinski A, Wang X, Tang S, Williams, Jr, JW. Metformin Use in Patients with Contraindications or 

Precautions. VA ESP Project #09-010; 2016.

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Center located at 

the Durham VA Medical Center, Durham, NC, funded by the Department of Veterans Affairs, Veterans Health 

Administration, Office of Research and Development, Quality Enhancement Research Initiative. The findings and 

conclusions in this document are those of the author(s) who are responsible for its contents; the findings and 

conclusions do not necessarily represent the views of the Department of Veterans Affairs or the United States 

government. Therefore, no statement in this article should be construed as an official position of the Department 

of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, consultancies, 

honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties) that 

conflict with material presented in the report.
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TABLE OF CONTENTS

EXECUTIVE SUMMARY .......................................................................................................... 1

Introduction ................................................................................................................................. 1

Methods....................................................................................................................................... 1

Data Sources and Searches ..................................................................................................... 1

Study Selection ....................................................................................................................... 1

Data Abstraction and Quality Assessment .............................................................................. 2

Data Synthesis and Analysis ................................................................................................... 2

Results ......................................................................................................................................... 2

Results of Literature Search .................................................................................................... 2

Summary of Results for Key Questions.................................................................................. 2

Discussion ................................................................................................................................... 3

Key Findings and Strength of Evidence ................................................................................. 3

Applicability ........................................................................................................................... 4

Research Gaps/Future Research ............................................................................................. 4

Conclusions ............................................................................................................................. 4

Abbreviations Table .................................................................................................................... 6

INTRODUCTION......................................................................................................................... 7

METHODS .................................................................................................................................... 9

Topic Development ..................................................................................................................... 9

Search Strategy ........................................................................................................................... 9

Study Selection ........................................................................................................................... 9

Data Abstraction ....................................................................................................................... 11

Quality Assessment ................................................................................................................... 12

Data Synthesis ........................................................................................................................... 12

Rating the Body of Evidence .................................................................................................... 13

Peer Review .............................................................................................................................. 13

RESULTS .................................................................................................................................... 14

Literature Flow.......................................................................................................................... 14

Key Question 1: For patients with type 2 diabetes and an apparent contraindication/precaution 

to metformin use (eg, renal insufficiency, congestive heart failure, chronic liver disease, or 

older age): ................................................................................................................................. 16

Key Findings ......................................................................................................................... 16

Rate of Lactic Acidosis with Metformin Use ....................................................................... 17

Lactic Acidosis with Metformin Use Compared with Other Hypoglycemic Medications ... 18

Quality of Evidence for Key Question 1............................................................................... 20

Summary of Findings ............................................................................................................ 20

Key Question 2: For patients with type 2 diabetes and an apparent contraindication/precaution 

to metformin use, what are the potential benefits and harms (other than lactic acidosis) of 

continued treatment with metformin? ....................................................................................... 21

Key Findings ......................................................................................................................... 21

Chronic Kidney Disease ....................................................................................................... 21

Congestive Heart Failure ...................................................................................................... 24

Chronic Liver Disease........................................................................................................... 27
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Older Adults .......................................................................................................................... 28

Quality of Evidence for Key Question 2............................................................................... 32

Summary of Findings ............................................................................................................ 32

SUMMARY AND DISCUSSION .............................................................................................. 34

Strength of Evidence ................................................................................................................. 34

Clinical and Policy Implications ............................................................................................... 36

Strengths and Limitations ......................................................................................................... 37

Future Research ........................................................................................................................ 38

Conclusions ............................................................................................................................... 39

REFERENCES ............................................................................................................................ 40

TABLES

Table 1. Lactic Acidosis Type Classification3 ........................................................................... 7

Table 2. Inclusion and Exclusion Criteria ................................................................................ 10

Table 3. Rate of LA with Metformin Use ................................................................................ 18

Table 4. Rate of LA with Metformin Use Compared with Other Hypoglycemic Medications 19

Table 5. Effects of Metformin on Mortality in Patients with CLD .......................................... 27

Table 6. Effects of Metformin on Mortality or MACE in Older Adults .................................. 28

Table 7. Effects of Metformin on A1c in Older Adults—RCTs .............................................. 30

Table 8. Effects of Metformin on Hypoglycemic Events in Older Adults ............................... 32

Table 9. Strength of Evidence for Effects of Metformin Use Versus 

Non-Metformin Use on Risk of LA (KQ 1b) ........................................................................... 35

Table 10. Strength of Evidence for Effects of Metformin Use Versus 

Non-Metformin Use on Mortality and MACE (KQ 2) ............................................................ 35

FIGURES

Figure 1. Literature Flow Chart ................................................................................................. 15

Figure 2. Meta-analysis of All-cause Mortality with Use of Metformin Versus 

Non-metformin Treatment Among Patients with CKDa,b .......................................................... 23

Figure 3. Meta-analysis of All-cause Mortality with Use of Metformin Versus 

Non-metformin Treatment Among Patients with CHFa

 ............................................................ 25

Figure 4. Meta-analysis of CHF Readmission with Use of Metformin Versus 

Non-metformin Treatment Among Patients with CHFa ............................................................ 26

Figure 5. Meta-analysis of Cardiovascular Mortality with Use of Metformin 

Versus Non-metformin Treatment Among Patients with CHFa ................................................ 26

APPENDIX A. FDA Safety Announcements for Metformin .......................................................46 

APPENDIX B. Search Strategy ...................................................................................................50 

APPENDIX C. Quality Assessment for Randomized Controlled Trials ......................................53 

APPENDIX D. Quality Assessment for Observational Studies ...................................................57 

APPENDIX E. Peer Review Comments/Author Responses ........................................................64 

APPENDIX F. Study Characteristics Tables ...............................................................................68 

APPENDIX G. Results for Older Adults by Study Design ..........................................................79 
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EXECUTIVE SUMMARY

INTRODUCTION

Metformin is a biguanide oral hypoglycemic used primarily for treating type 2 diabetes mellitus 

(T2D). Evidence suggests that, in addition to improving glycemic control, metformin is 

associated with improved all-cause and cardiovascular mortality and decreased risk of some 

cancers. However, clinicians have been advised by the U.S. Food and Drug Administration 

(FDA) to exercise caution in prescribing metformin to individuals with chronic kidney disease 

(CKD), unstable congestive heart failure (CHF), chronic liver disease (CLD), and older age due 

to perceived risk of side effects, including lactic acidosis (LA).

Recent literature highlights the rarity of metformin-associated LA and supports the cautious 

expansion of metformin use. In addition, in April 2016 the FDA modified its position on CKD to 

extend use of metformin to some patients with moderate CKD. Yet there remain uncertainties 

regarding the risks and benefits of metformin use in populations with CKD, CHF, CLD, and 

older age. For this reason, we conducted a systematic review and meta-analysis in order to 

determine the answers to the following key questions:

KQ 1. For patients with type 2 diabetes and an apparent contraindication or precaution to 

metformin use (eg, renal insufficiency, congestive heart failure, chronic liver disease, or older 

age):

a. What is the rate of lactic acidosis in patients taking metformin?

b. How does the rate of lactic acidosis in patients taking metformin compare with the rate in 

patients taking other hypoglycemics?

KQ 2. For patients with type 2 diabetes and an apparent contraindication or precaution to 

metformin use, what are the potential benefits and harms (other than lactic acidosis) of continued 

treatment with metformin?

METHODS

Data Sources and Searches

We searched MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (KQ 

2 only), Embase, the International Pharmaceutical Abstracts, and ClinicalTrials.gov. We also 

evaluated the reference lists of systematic or nonsystematic reviews and queried Bristol-Myers 

Squibb, the manufacturer of Glucophage (branded formulation of metformin), for relevant 

studies.

Study Selection

Using prespecified inclusion/exclusion criteria, the abstracts of RCTs identified through our 

search were reviewed by 2 reviewers and those deemed relevant underwent full-text review. 

Articles meeting eligibility criteria were included for data abstraction.
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Data Abstraction and Quality Assessment

Key characteristics abstracted by one reviewer and overread by another were patient descriptors, 

setting, definitions of contraindications or precautions of interest, metformin dose, 

cointerventions, comparator, and outcomes. Quality was assessed independently by 2 reviewers 

using the Cochrane Risk of Bias tool for RCTs and the key quality criteria described in the 

Agency for Healthcare Research and Quality’s (AHRQ’s) Methods Guide for Effectiveness and 

Comparative Effectiveness Reviews, adapted to this specific topic and customized to 

observational studies. 

Data Synthesis and Analysis

We summarized the primary literature using relevant data abstracted from the eligible studies 

and determined the feasibility of completing a quantitative synthesis (ie, meta-analysis) to 

estimate summary effects. For all analyses, we focused on studies at low or moderate risk of bias 

and analyzed RCTs and observational studies as well as patients with different contraindications 

or precautions to metformin separately. Quantitative synthesis was feasible only for mortality 

and major adverse cardiovascular event (MACE) outcomes using a random-effects model to 

generate hazard ratios. When quantitative synthesis was not feasible, we analyzed the data 

qualitatively. Strength of evidence (SOE) was assessed using the approach described in the 

Agency for Healthcare Research and Quality (AHRQ)’s Methods Guide.

RESULTS

Results of Literature Search

We reviewed a total of 4,849 abstracts and 523 full-text articles. Of these, 37 (29 observational 

studies and 8 RCTs) were retained for data abstraction. By KQ, 9 studies addressed KQ 1 and 32 

studies addressed KQ 2. By precaution, studies reported data relevant to older adults (n = 16), 

patients with CHF (n = 11), patients with CKD (n = 9), and patients with CLD (n = 3). 

Summary of Results for Key Questions

Since a 2010 Cochrane review, there are limited new data examining the rate of LA with 

metformin use; however, we found 9 contemporary observational studies reporting on this 

outcome in individuals with an identified precaution or contraindication to metformin use.

KQ 1a: Limited data (2 studies) suggest the incidence of LA in metformin users who have CKD 

is slightly higher than the upper bounds (4.3/100,000) reported in the Cochrane review. The 

limited data (2 studies) on incidence rates of LA among older adults are inconclusive. The risk of 

bias for these studies was judged to be high. No studies reported incidence rates for individuals 

with CHF or CLD. 

KQ 1b: Five studies comparing rates of LA with metformin use versus non-metformin diabetes 

treatment do not suggest a higher rate of LA with metformin use among individuals with CKD, 

CHF, or CLD. The risk of bias for these studies was judged to be low (n = 2) or moderate (n = 

3). No study reported this outcome for older adults without one of these comorbid conditions.
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Based on our synthesis of observational evidence, the risk of LA with metformin use among 

individuals with a contraindication or precaution appears to be low (ie, not higher than the risk of 

LA with other hypoglycemic medications).

KQ 2: Among patients with T2D and CKD, metformin use is associated with a significantly 

lower risk of all-cause mortality (n = 5); limited evidence was identified for major adverse 

cardiovascular events (MACE, n = 2). Among patients with T2D and CHF, metformin use is also 

associated with a significantly lower risk of all-cause mortality (n = 11) and heart failure 

readmission (n = 4), but risk of cardiovascular mortality did not differ (n = 3). Among patients 

with T2D and CLD, limited evidence suggests a lower risk of all-cause mortality (n = 3) may be 

associated with metformin use. There was no evidence identified for MACE in relation to CLD. 

Among patients with T2D and older age (generally age 65 years), limited evidence suggests 

that metformin is not associated with a higher risk of all-cause mortality (n = 4), MACE (n = 1),

or hypoglycemia (n = 6). These results are all in comparison to non-metformin treatment.

While limited evidence suggests that progressively lower estimated glomerular filtration rate 

(eGFR) may diminish the mortality benefit associated with metformin use, the impact of CHF 

severity, CLD severity, and increasing older age on the effects of metformin is unclear. No 

evidence was identified regarding the effects of metformin on glycemic control, lipid control, 

weight, hypoglycemia, or vitamin B12 deficiency among patients with medically treated T2D 

and CKD, CHF, or CLD.

Based on our quantitative syntheses of observational evidence, metformin use is associated with 

a lower risk of all-cause mortality when compared with non-metformin treatment among patients 

with medically treated T2D and CKD or CHF. Limited evidence is available regarding all-cause 

mortality in CLD, but qualitative synthesis of available evidence suggests that metformin may be 

beneficial in this population. Data on the effects of metformin in older adults are limited, but 

does not indicate increased harm from the use of metformin compared to nonuse.

DISCUSSION

Key Findings and Strength of Evidence

Consistent with prior reviews, we found that metformin use is associated with an overall low risk 

of LA among individuals with traditional contraindications or precautions, with the exception 

that identified studies did suggest that patients with CKD may experience a slightly higher rate 

of LA while using metformin compared to general diabetes populations; this risk appears highest 

in individuals with eGFR <30. Based on limited available evidence, the comparative risk of LA 

associated with metformin use among patients with CKD, CHF, or CLD does not appear higher 

than the risk with use of other hypoglycemic medications. We found no comparative studies 

examining LA in older adults.

When used to treat T2D among patients with CKD or CHF, metformin is associated with a lower 

risk of all-cause mortality and CHF readmission compared to non-metformin therapies. Based on 

limited evidence, we found no associations between use of metformin and other outcomes of 

interest (MACE, glycemic control, lipid control, weight, hypoglycemia, or vitamin B12 

deficiency) in T2D populations with historical contraindications or precautions.
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Using data from 209 RCTs, a prior Cochrane review identified no cases of LA; however, these 

trials did not seek out individuals with the contraindications or precautions of interest. We 

identified 5 observational studies reporting LA in patients using metformin compared to nonmetformin users. For cases of CKD, findings were inconsistent, but suggest that rates of LA in 

patients with CKD may be higher than metformin users overall. For CHF and CLD, there were 

no cases of LA. For patients with a contraindication or precaution to metformin, we judged the 

SOE insufficient to determine the rate of LA for metformin users versus non-users. In relation to 

all-cause mortality, in CKD, CHF, and older adults, there are uniformly fewer deaths among 

patients taking metformin (low SOE).

Applicability

In April 2016, the FDA issued a statement supporting metformin initiation in patients with an 

eGFR >45 mL/min/1.73m2 and continuation with appropriate monitoring in patients with an 

eGFR >30-45 mL/min/1.73m2. In the wake of these recent changes in FDA labeling, prescribing

of metformin will undoubtedly increase. This systematic review provides a comprehensive, upto-date evaluation of existing literature regarding multiple key outcomes associated with 

metformin use in T2D populations with traditional precautions. Our findings will directly inform 

clinicians’ prescribing practices for T2D patients with traditional restrictions to receiving this 

medication. In addition to informing clinician practice, this review may help inform the revision 

of prescribing guidelines within VA and professional societies.

Research Gaps/Future Research

The primary gap in the current evidence regarding metformin use in populations with traditional 

contraindications or precautions is the lack of randomized trials in this domain; large simple 

pragmatic trials could fill this gap. Even without RCTs, new observational studies will remain 

important to ensure that rates of metformin-associated LA do not rise as metformin prescribing

increases among populations with traditional contraindications or precautions (especially CKD). 

Additional, observational studies will also be useful in comparing metformin to newer diabetes 

agents in these populations. Additional studies focusing specifically on cohorts with eGFR 30-45

mL/min/1.73m2 or even <30 mL/min/1.73m2 would further inform prescribing of metformin in 

these groups, and refinement of clinical guidelines. Data regarding the impact of precaution 

severity in CHF, CLD, and older age are sparse, and further observational research could address 

these gaps. The possibility of tailoring prescribing recommendations based on the severity of 

historical contraindications or precautions would also benefit from further research. Finally, 

future research is warranted to explore CLD and outcomes of interest beyond mortality. It will 

also be crucial to evaluate whether the mortality benefit associated with metformin use persists 

as prescribing in populations with historical contraindications or precautions expands.

Conclusions

Based on limited evidence, the rate of LA associated with metformin use among patients with 

historical contraindications or precautions does not appear higher than that of other diabetes 

medications. Metformin appears to be associated with reduced all-cause mortality in patients 

with CKD and patients with CHF, and appears to be associated with reduced CHF readmission. 

Though data are otherwise limited, other risks of metformin use do not appear higher than those 

associated with other diabetes medications among patients with historical contraindications or 
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precautions. Despite this review’s limitations, our findings support recent FDA labeling changes, 

may inform clinical practice, and point toward important areas for future research.
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ABBREVIATIONS TABLE

AHRQ Agency for Healthcare Research and Quality

CI Confidence interval

CHF Congestive heart failure

CKD Chronic kidney disease

CLD Chronic liver disease

eGFR Estimated glomerular filtration rate

ESP Evidence-based Synthesis Program

GRADE Grading of Recommendations Assessment, Development, and Evaluation

HSR&D Health Services Research & Development

KQ Key question

LA Lactic acidosis

MACE Major adverse cardiovascular event

MI Myocardial infarction

MD Mean difference

MeSH Medical subject heading

PICOTS Population, intervention, comparator, outcome, timing, and setting

QUERI Quality Enhancement Research Initiative

RCT Randomized controlled trial

SMD Standardized mean difference

SOE Strength of evidence

T2D Type 2 diabetes

VA Veterans Affairs

VHA Veterans Health Administration
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EVIDENCE REPORT 

INTRODUCTION 

Metformin is a biguanide oral hypoglycemic used primarily for treating type 2 diabetes mellitus 

(T2D). Evidence suggests that, in addition to improving glycemic control, metformin is

associated with improved all-cause and cardiovascular mortality1

 and decreased risk of some 

cancers (eg, breast cancer).

2 Despite the potential benefits, since metformin was introduced in the 

United States in the mid-1990s, clinicians have been advised to exercise caution in prescribing 

the drug to individuals with certain comorbidities due to perceived risks of serious side effects, 

including LA. Lactic acidosis (LA) is defined as blood lactate concentration >45mg/dl 

(5.0mEq/L), decreased blood pH, and electrolyte disturbances with an increased anion gap. It

may result from lactate overproduction because of inadequate tissue oxygen delivery or without 

overt tissue hypoperfusion. The LA type classifications are explained in Table 1. 

Table 1. Lactic Acidosis Type Classification3

 

Type A-LA: Clinical Evidence of Inadequate Tissue Oxygen Delivery

Anaerobic muscular activity (eg, sprinting, generalized convulsions)

Tissue hypoperfusion (eg, shock: septic, cardiogenic, or hypovolemic; hypotension; cardiac 

arrest; acute heart failure; regional hypoperfusion, especially mesenteric ischemia; malaria)

Reduced tissue oxygen delivery or utilization (eg, hypoxemia, carbon monoxide poisoning, 

severe anemia)

Type B-LA: No Clinical Evidence of Inadequate Tissue Oxygen Delivery

Type B1: Associated with underlying diseases (eg, ketoacidosis, leukemia, lymphoma, AIDS)

Type B2: Associated with drugs and toxins (eg, phenformin, cyanide, beta-agonists, 

methanol, nitroprusside infusion, ethanol intoxication in chronic alcoholics, antiretroviral 

drugs)

Type B3: Associated with inborn errors of metabolism (eg, congenital forms of LA with 

various enzyme defects such as pyruvate dehydrogenase deficiency)

Note: Table does not include all causes of LA. 

Among the most serious side effects of metformin is metformin-associated LA, which is a rare

(approximately 0.03 cases per 1000 person-years) but potentially highly fatal type B-LA.

4 

Metformin is excreted through the kidneys, and most cases of metformin-associated LA have 

occurred in the setting of inappropriate dosing, significant kidney impairment, sepsis, 

hypovolemia, excess alcohol intake, hepatic insufficiency, age greater than 80 years, or 

acute/decompensated congestive heart failure (CHF).5,6 As such, the FDA specifies chronic 

kidney disease (CKD) with low estimated glomerular filtration rate (eGFR) as a contraindication 

to metformin use, and it lists acute or unstable CHF, older age, and hepatic impairment as 

precautions for use.7,8 Despite these warnings, there are efforts to expand the use of metformin, 

and currently more than 50% of metformin users may have an ongoing contraindication or 

precaution for its use.

9,10 

In 2006, the FDA relaxed its warning regarding CHF and metformin use and removed acute or 

unstable CHF as a contraindication. More recently, in April 2016, the definition of CKD used by 

the FDA in the boxed warning was modified (Appendix A).11 Historically, metformin use was to 

be avoided in individuals with a serum creatinine ≥1.5mg/dL for men and ≥1.4 mg/dL for

women. Serum creatinine is known to be a poor marker of kidney function.12 Consequently, this 
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guideline discouraged use of metformin in many individuals with relatively normal kidney 

function. Therefore, the kidney function cutoff was revised to an eGFR of 45 mL/min/1.73m2 if 

renal function is monitored every 3 months to 6 months, but still contraindicated if eGFR is <30

mL/min/1.73m2, consistent with recent clinical guidelines for metformin use and best practices 

for estimating kidney function.11,13,14 An estimated one million additional patients became 

eligible to use metformin as a result of this change.15

Recent literature highlights the rarity of metformin-associated LA and supports the cautious 

expansion of metformin use. Most notably, a 2010 Cochrane systematic review found no 

association between metformin use and fatal or nonfatal LA,

16 and a 2014 systematic review

found the incidence of LA among metformin users to be indistinguishable from background 

population rates, ranging from approximately 3 per 100,000 person-years to 10 per 100,000 

person-years.5 Yet there remain uncertainties regarding metformin’s appropriate use, and the 

benefit relative to the harm in populations with CKD, CHF, hepatic impairment (eg, chronic liver 

disease), and older age are not well understood. For this reason, we conducted a systematic 

review and meta-analysis in order to determine (1) the rates of LA associated with metformin use 

in patients with T2D and (2) the benefits and harms of metformin use in the presence of 

traditional contraindications or precautions. 
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METHODS

TOPIC DEVELOPMENT

The key questions (KQs) for this systematic review were developed after a topic refinement 

process that included a preliminary review of published, peer-reviewed literature; consultation 

with internal partners and investigators; and consultation with content experts and key VA 

stakeholders.

The final KQs were:

KQ 1. For patients with type 2 diabetes and an apparent contraindication/precaution to 

metformin use (eg, renal insufficiency, congestive heart failure, chronic liver disease, or older 

age):

a. What is the rate of lactic acidosis in patients taking metformin?

b. How does the rate of lactic acidosis in patients taking metformin compare with the rate in 

patients taking other hypoglycemics?

KQ 2. For patients with type 2 diabetes and an apparent contraindication/precaution to 

metformin use, what are the potential benefits and harms (other than lactic acidosis) of continued 

treatment with metformin?

We followed a standard protocol for this review, and each step was pilot-tested to train and 

calibrate study investigators. The PROSPERO registration number is CRD42016027708.

SEARCH STRATEGY

In consultation with an expert librarian, we conducted searches of MEDLINE (via PubMed), the 

Cochrane Central Register of Controlled Trials (KQ 2 only), Embase, and the International 

Pharmaceutical Abstracts in November 2015. The exact search strategies are in Appendix B. We 

also searched ClinicalTrials.gov for relevant completed and ongoing studies.

We also evaluated the reference lists of systematic or nonsystematic reviews and queried BristolMyers Squibb, the manufacturer of Glucophage (branded formulation of metformin), for relevant 

studies. We used a combination of MeSH keywords and selected free-text terms to search titles 

and abstracts. All citations were imported into 2 electronic databases (for referencing, EndNote®

Version X7, Thomson Reuters, Philadelphia, PA; for data abstraction, DistillerSR; Evidence 

Partners Inc., Manotick, ON, Canada).

STUDY SELECTION

Using prespecified inclusion/exclusion criteria (Table 2), titles and abstracts of RCTs identified 

through our search were reviewed by 2 reviewers for potential relevance to the KQs. Articles 

included by either reviewer underwent full-text screening. At the full-text screening stage, 2

independent reviewers were required to agree on a final inclusion/exclusion decision. 

Disagreements were resolved by discussion or by a third investigator. Of note, prior to excluding 

any potentially eligible study whose primary analysis did not address a population with a 
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metformin contraindication or precaution, we specifically examined the full text for analyses of 

relevant subgroups. Articles meeting eligibility criteria were included for data abstraction.

Table 2. Inclusion and Exclusion Criteria

Study Characteristic Inclusion/Exclusion Criteria

Population Adults (≥18 years of age) with T2D (using criteria valid at the time of the 

study) and one of the following contraindications/precautions to 

metformin use: CKD, CHF, CLD, or older age as defined by authors of 

the primary study.

Exclusions: 

Mixed samples where less than 80% have one or more of the 

specified contraindications/precautions, and results are not 

reported by subgroup.

 Studies where less than 80% of the sample has T2D. The 

rationale is that relatively homogeneous samples of the population 

of interest are required to evaluate metformin effects. 

Samples with prediabetes or metabolic syndrome, gestational 

diabetes mellitus, acute kidney injury in the absence of CKD, endstage renal disease on hemodialysis, and contrast exposure (eg, 

contrast-enhanced imaging procedures). CKD may be defined as 

an elevated creatinine or eGFR <60 mL/min/1.73m2

; 

microalbuminuria alone is not considered CKD for the purposes of 

this review.

Interventions Metformin use alone or in combination with other glucose-lowering 

treatment.

Exclusion: Phenformin

Comparators KQ 1a: None, or any inactive control or active comparator

KQ 1b and KQ 2: Non-metformin oral or injectable hypoglycemic 

medication(s) in the presence of a traditional contraindication or 

precaution to metformin use

Exclusion: Studies that did not allow evaluation of the effect of 

metformin (eg, studies that compared metformin plus a hypoglycemic 

medication to metformin plus a different hypoglycemic medication)

Outcomes KQ 1a and 1b: Incidence of fatal and nonfatal LA or metforminassociated LAa

KQ 2: Benefits evaluated include glycemic control (ie, A1c), lipid 

control, major adverse cardiovascular events (MACE) (eg, MI, 

CHF hospitalization), cardiovascular-related mortality, and allcause mortality; harms included hypoglycemia and weight gain 

Exclusion: Studies that reported only metformin clearance, metformin 

levels, or lactate levels without one of the specified outcomes of interest

Timing Studies reporting outcomes at ≥28 days (approximately 1 month) 

following initiation of metformin or switching to another medication

Setting Outpatient or population-based. Studies that identified hospitalized 

patients with metformin-associated LA and were able to estimate a rate 

based on outpatient or population-based samples were eligible.
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Study Characteristic Inclusion/Exclusion Criteria

Study design KQ 1a: Clinical trials, prospective and retrospective cohort studies, 

and pharmacovigilance studies. Excluded were case reports, caseseries, and cross-sectional studies because such studies cannot 

provide a rate of LA. 

KQ 1b: Clinical trials, comparative prospective and retrospective 

cohort studies, case-control studies, and pharmacovigilance 

studies. Excluded were case reports, case-series, and crosssectional studies.

KQ 2: RCTs, nonrandomized clinical trials, and comparative 

prospective and retrospective cohort studies

Publication type Full publications in English-language, peer-reviewed journals

Exclusions: Meeting abstracts, letters, editorials, and dissertations

Limits Studies were limited to the 34 countries that are part of the Organization 

for Economic Cooperation and Development.17 The rationale is to limit to 

countries where T2D is more prevalent and the general medical care is 

similar to that in United States.

For KQ 1a and KQ 1b, the search was limited to 2009 through the 

present. For KQ 2, we searched from 1994, the year that metformin was 

approved by the FDA, through the present. A high-quality Cochrane 

review (search date October 200916) included all clinical trials in patients 

with T2D and all observational cohort studies evaluating ≥1 month of 

metformin use. Outcomes were death due to LA, nonfatal LA, and blood 

lactate levels. Other relevant reviews13,18 have even more recent 

searches. a LA is defined as blood lactate concentration >45mg/dl or 5.0mEq/L, decreased blood pH, and electrolyte 

disturbances with an increased anion gap. Metformin-associated LA is defined as meeting the definition for LA plus 

either (a) elevated metformin level or (b) investigator judgment that LA is metformin-induced. We abstracted 

information to determine if outcomes conformed or deviated from these definitions.

Abbreviations: CHF = congestive heart failure; CKD = chronic kidney disease; CLD-chronic liver disease; eGFR = 

estimated glomerular filtration rate; LA = lactic acidosis; MACE = major adverse cardiovascular event; MI = 

myocardial infarction; RCT = randomized controlled trial; T2D = type 2 diabetes

DATA ABSTRACTION

Data from published reports were abstracted into a customized DistillerSR database by one 

reviewer and overread by a second reviewer. Disagreements were resolved by discussion or by a 

third investigator. Key characteristics abstracted were patient descriptors (including age, sex, 

race, and specific contraindication/precaution to metformin), setting, metformin dose, 

cointerventions (eg, other hypoglycemics), comparator, and outcomes which we selected in 

conjunction with our stakeholders and technical expert panel. For observational studies, we 

abstracted unadjusted and adjusted outcomes. Other key information included definitions related 

to contraindications/precautions (eg, definition of CKD and methods for determining 

CKD/estimating eGFR such as the Modification of Diet in Renal Disease formula19 or the 

Cockcroft-Gault formula20). We treated multiple publications from a single study as a single data 

point, prioritizing the longest-term, most complete, and most appropriately analyzed results. 

When critical data were missing or unclear in published reports, we requested supplemental data 

from manuscript authors. Key features relevant to applicability included the match between the 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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sample and target populations (eg, metformin contraindication/precaution, age, concurrent 

treatments, or Veteran status).

QUALITY ASSESSMENT

Quality assessment was done independently by 2 investigators. Disagreements were resolved by 

consensus between the 2 investigators or, when needed, by arbitration by a third investigator.

We used the Cochrane Risk of Bias tool for RCTs21 and the key quality criteria described in the 

Agency for Healthcare Research and Quality’s (AHRQ’s) Methods Guide for Effectiveness and 

Comparative Effectiveness Reviews,

22 adapted to this specific topic and customized to 

observational studies.23 For RCTs, these criteria are adequacy of randomization and allocation 

concealment; blinding of participants, personnel, and outcomes assessment; whether incomplete 

data were addressed appropriately; selective reporting, and other bias. We assigned a summary 

risk of bias score (low, unclear, or high) to individual studies (Appendix C). For observational 

studies, we used a tool customized to this project that addresses risk of bias from selection, 

performance, attrition, detection, and selective outcome reporting (Appendix D).

24

DATA SYNTHESIS

We summarized the primary literature using relevant data abstracted from the eligible studies. 

Summary tables describe the key study characteristics of the included studies: metformin 

contraindication/precaution (including severity such as CKD stage), patient demographics 

(including age), and details of the intervention and comparator. When necessary,

25,26,25,26 relevant

hazard ratios (HRs) with the same reference group were pooled in a weighted fashion based on 

the subject counts in each category, incorporating an approximation of the correlation resulting 

from the shared reference. In the absence of a reported HR,

27 we estimated the HR and variance 

from the reported frequencies and odds ratio (OR) using an established approach.

28 We then 

determined the feasibility of completing a quantitative synthesis (ie, meta-analysis) to estimate 

summary effects. For all analyses, we analyzed RCTs separately from observational studies.29

We aggregated outcomes when there were at least 3 studies with the same outcome, based on the 

rationale that one or 2 studies do not provide adequate evidence for summary effects. Analyses 

were conducted separately for patients with different contraindications or precautions to 

metformin (eg, CKD vs CHF), using rates adjusted for potential confounders. We planned to 

conduct subgroup analyses by severity of contraindication/precaution (eg, CKD stage), by single 

(metformin monotherapy) versus combined treatment (eg, metformin plus other hypoglycemics 

with or without metformin), and by comparator (lifestyle or placebo vs other hypoglycemics). 

However, there were too few studies to support the planned subgroup analyses.

Studies reported dichotomous outcomes (eg, LA, mortality, hypoglycemic events) and 

continuous outcomes (eg, A1c, weight, lipid values). Quantitative synthesis was feasible only for 

mortality and major adverse cardiovascular event (MACE) outcomes. These outcomes were 

combined using a random-effects model to generate summary hazard ratios. For analyses with 

few (n<20) studies, we used the Knapp-Hartung approach to adjust the standard errors of the 

estimated coefficients.30,31 Sensitivity analyses omitted studies with severe disease (eg, eGFR < 

30ml/min/1.73m2. We evaluated statistical heterogeneity using visual inspection and Cochran’s 

Q and I2 statistics. Publication bias was assessed using funnel plots (when there were >10 studies 

in an analysis).
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When quantitative synthesis was not feasible, we analyzed the data qualitatively. We gave more 

weight to the evidence from higher-quality studies with more precise estimates of effect. A 

qualitative synthesis focuses on documenting and identifying patterns in efficacy and safety of 

the interventions across conditions and outcome categories. We analyzed potential reasons for 

inconsistency in treatment effects across studies by evaluating differences in the study 

population, intervention, comparator, and outcome definitions.

RATING THE BODY OF EVIDENCE

Strength of evidence (SOE) was assessed using the approach described in the Agency for 

Healthcare Research and Quality (AHRQ)’s Methods Guide.

22 We limited Grading of 

Recommendations Assessment, Development and Evaluation (GRADE) ratings32 to those 

outcomes identified by the stakeholders and technical expert panel as critical to decision making. 

These included nonfatal and fatal LA and mortality. In brief, this approach assesses 4 domains: 

risk of bias, consistency, directness, and precision. Additional domains were used when 

appropriate and included coherence, dose-response association, impact of plausible residual 

confounders, strength of association (magnitude of effect), and publication bias. These domains 

were considered qualitatively, and a summary rating was assigned after discussion by 2

investigators as high, moderate, or low strength of evidence. In some cases, high, moderate, or 

low ratings were impossible or imprudent to make. In these situations, a grade of insufficient was

assigned. This 4-level rating scale consists of the following definitions:

High—We are confident that the true effect lies close to the estimate of effect.

Moderate—We are moderately confident of the effect estimate: The true effect is likely 

to be close to the estimate of effect, but there is a possibility that it is substantially 

different.

Low—Our confidence in the effect estimate is limited: The true effect may be 

substantially different from the estimate of the effect.

Insufficient—We have very little confidence in the effect estimate: The true effect is 

likely to be substantially different from the estimate of effect.

PEER REVIEW

A draft of this report was reviewed by technical experts and clinical leadership. A transcript of 

their comments and our responses is provided in Appendix E.
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RESULTS

LITERATURE FLOW 

Figure 1 shows the flow of articles through the literature search and screening process. The 

literature search identified 4,841 unique citations from a combined search of MEDLINE® (via 

PubMed®), the Cochrane Registry of Controlled Trials, Embase®, and International 

Pharmaceutical Abstracts. An additional 8 articles were identified from manual searches of 

bibliographies and current literature published after the search date for a total of 4,849 unique 

citations. After applying inclusion and exclusion criteria at the title-and-abstract screening level, 

523 full texts were retrieved for further review. Of these, 37 were retained for data abstraction.

We attempted to contact 13 authors for additional study information; however, 7 could not be 

reached, and the remaining 6 all replied that the data were not available. 

Among the 37 included studies, 29 were observational studies and 8 were randomized controlled 

trials (RCTs), of which one was a companion paper. Some studies reported results applicable to 

more than one key question (KQ) or one precaution or contraindication. By KQ, 9 studies 

addressed KQ 1 and 32 studies addressed KQ 2. By precaution, studies reported data relevant to 

older adults (n = 16), patients with CHF (n = 11), patients with CKD (n = 9), and patients with 

CLD (n = 3). Most studies were conducted in samples from Europe and used a retrospective 

cohort design; 4 studies were conducted in Veteran samples. Of note, we identified no ongoing 

studies meeting our inclusion criteria in ClinicalTrials.gov. 
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Figure 1. Literature Flow Chart 

Search results: 4849 = 

4841 references* from 

search + 8 manually 

identified 

Pulled for full text review: 

523 references

Included studies:

37 references**

Excluded at title and abstract screening stage:

4326 references

Excluded at full text review: 486 references

Studies published prior to year 2009: 16

Non-English publication: 4

Comments, editorials, or meeting abstracts: 57

Not study design of interest: 16

Not OECD countries: 11

Not population of interest: 213

No outcomes of interest: 169

KQ 1a only:

4 references

KQ 1b only:

1 reference

KQ 2 only:

27 references

Both KQ 1a and 

1b 

1 reference

* Search results are from Embase (2512), PubMed (2312), Cochrane (17). 

** The report’s reference list includes all the studies (CHF/cardiovascular studies, n = 18; the remaining 

studies are elderly). One of the included studies is a companion paper.

All KQs (1a, 1b 

and 2) 

4 references
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KEY QUESTION 1: For patients with type 2 diabetes and an apparent 

contraindication/precaution to metformin use (eg, renal insufficiency, 

congestive heart failure, chronic liver disease, or older age):

a. What is the rate of lactic acidosis in patients taking metformin?

b. How does the rate of lactic acidosis in patients taking metformin 

compare with the rate in patients taking other hypoglycemics?

Key Findings

There are limited new data examining the rate of lactic acidosis (LA) with metformin use 

since the 2010 Cochrane review; however, a small number of contemporary studies have 

reported on this outcome in individuals with an identified precaution or contraindication 

to metformin use.

KQ 1a: Limited data suggest that the incidence of LA in metformin users who have 

chronic kidney disease (CKD) is slightly higher than the upper bounds (4.3/100,000) 

reported in the Cochrane review. The limited data on incidence rates of LA among older 

adults are inconclusive. No studies reported incidence rates for individuals with CHF or 

chronic liver disease (CLD).

KQ 1b: The data comparing rates of LA with metformin use versus non-metformin 

diabetes treatment do not suggest a higher rate of LA with metformin use among 

individuals with CKD, CHF, or CLD. No study reported this outcome for older adults 

without one of these comorbid conditions.

Recommendations regarding the use of metformin in the treatment of type 2 diabetes (T2D) are 

limited by concerns of the development of fatal or nonfatal LA among individuals with a 

contraindication to metformin therapy. In 2010, Salpeter et al published a scientifically rigorous 

Cochrane review of studies through 2009 describing the rate of fatal and nonfatal LA with 

metformin use in patients with T2D.16 The authors found no cases of LA in 70,490 patient-years 

of metformin use using pooled data from 347 comparative trials and cohort studies. Using 

Poisson statistics, the upper 95% confidence interval (CI) for the rate of LA was estimated at 4.3 

per 100,000 person-years in metformin users and 5.4 per 100,000 person-years in nonusers.

However, there was insufficient information to estimate the number of participants studied with 

renal insufficiency, cardiovascular diseases, or liver disease. As an update to those findings, our 

review describes results in patients with a precaution/contraindication to metformin from 

publications in years 2009 through 2015. 

Since 2009, 9 observational studies have evaluated the rate of LA in individuals with T2D taking 

metformin and a contraindication/precaution to its use.25,33-40 We did not identify any RCTs 

enrolling patients with a precaution/contraindication or reporting relevant subgroup analyses for 

this outcome. Seven of the 9 studies were conducted in Europe,25,33-35,37,39,40 one in North 

America,38 and one in Japan.36 All 9 studies evaluated the rate of LA in individuals taking 

metformin; 5 studies compared the rate of LA in metformin users with the rate in individuals 

taking other hypoglycemics.25,34,35,38,40 Due to significant heterogeneity across studies and 

metformin precautions, a meta-analysis was not performed and studies were synthesized 

qualitatively. 
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For KQ 1, we present the detailed results by condition, starting with incidence (KQ 1a) and then 

comparison (KQ 1b). Details on study characteristics are in Appendix F.

Rate of Lactic Acidosis with Metformin Use 

Four studies examined the rate of LA among individuals taking metformin alone or in 

combination with another diabetic medication.33,36,37,39 There were no studies evaluating the 

individual effect of metformin on the occurrence of LA among individuals with CHF or CLD.

Chronic Kidney Disease

Two studies focused on the rate of LA in individuals with CKD.33,39 Of these, one prospective 

study with high risk of bias (ROB) included 588 French patients older than age 65 and evaluated 

the appropriateness of metformin dosing based on baseline estimated glomerular filtration rate 

(eGFR), which was derived using Cockcroft-Gault corrected for body surface area, or CKD-EPI 

estimating equations.39 Over an average follow-up of 3 years, there were no reported deaths due 

to LA irrespective of the appropriateness of metformin dosing. The study does not comment on 

the occurrence of nonfatal LA and does not present a time-adjusted analysis. 

The other study used records from a large UK database to examine the rate of LA in individuals 

on metformin with normal, mildly impaired, moderately impaired, or severely impaired renal 

function.33 CKD categories were based on diagnosis code of CKD stage or eGFR. This 

retrospective, high ROB study included 77,601 patients and 337,590 patient-years, during which 

there were 35 LA events (captured by ICD-9 code) over an average follow-up of 4.35 years. The 

overall rate of LA in individuals receiving metformin was 10.37 per 100,000 patient years (95% 

CI 7.22 to 14.42), higher than the estimate reported in the Cochrane review. The rate of LA by 

eGFR category was 7.61, 4.64, 17.18, and 39.0 per 100,000 patient-years among eGFR >90 

(normal), >60 to ≤90 (mildly impaired), >30 to ≤60 (moderately impaired), and ≤30 

ml/min/1.73m2 (severely impaired), respectively. There were no statistically significant 

differences in the incidence rate ratio (IRR) of LA across mildly, moderately, and severely

impaired renal function compared with normal renal function (IRR 0.61 [95% CI 0.12 to 5.26], 

2.27 [0.56 to 20.0], 5.26 [0.37 to 71.43], respectively), but confidence intervals were wide and 

did not exclude a clinically significant difference.

Older Adults

Two studies examined the rate of LA among older metformin users. One small 

pharmacovigilance study with high ROB evaluated the rates of elevated lactate or LA among 180 

Japanese adults ≥65 years of age retrospectively studied for one year.36 The most commonly 

used metformin dose was 750mg per day. There was no significant difference in elevated lactate 

level between elderly and nonelderly individuals, and no cases of LA were identified. A second 

study used a central Swedish registry to retrospectively identify the occurrence of LA (lactate 

levels >5mmol/L and serum pH <7.35).37 Median age was 67 (Table 3). Over 2 years, there were 

3 cases of LA (ages 65, 73, 75), among 5,408 individuals (equivalent to 27.7 per 100,000 person 

years), one of which was found to have metastatic pancreatic cancer and died the subsequent 

day. This is substantially higher than the rate of LA reported in the Cochrane review.
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Table 3. Rate of LA with Metformin Use

Study

Country

Precaution

Analysis Sample Outcome

Becquemont, 201539

France

CKD: eGFR category based 

on metformin adaptation

n = 588

Fatal LA: none over a mean follow-up of 3 

years

Richy, 201433

UK

CKD: eGFR >90, >60-90, 

>30-60, <30

n = 77,601

LA based on ICD-9: 10.3 per 100,000 

patient years over a mean follow-up of 4.35 

years. Rates did not differ by category of 

renal impairment

Ito, 201436

Japan

Older adults ≥65

n = 180

LA based on laboratory data: none over

1 year follow-up

No difference in lactate levels

Sterner, 201237

Sweden

Older adults

n = 5,408

LA based on lactate >5mmol/L and pH 

<7.35: 3 cases over 2 year follow-up

Abbreviations: CHF = congestive heart failure; CKD = chronic kidney disease; eGFR = estimated glomerular 

filtration rate; ICD = International Classification of Diseases; LA = lactic acidosis; ROB = risk of bias

Lactic Acidosis with Metformin Use Compared with Other Hypoglycemic 

Medications

Five studies evaluated the rate of LA with metformin use compared with other hypoglycemic 

medications.25,34,35,38,40 There were no studies comparing the rate of LA with metformin use 

versus other hypoglycemic medications in older adults. 

Chronic Kidney Disease

Two studies with moderate ROB compared the rate of LA with metformin use versus other 

hypoglycemic medications among individuals with CKD.34,40 The first study, performed in a 

Swedish pharmaceutical database, was a retrospective cohort study using a composite definition 

of acidosis/serious infection, categorized as fatal or any.40 Compared with metformin 

monotherapy, the risk of the any acidosis/serious infection was increased with insulin 

monotherapy (HR 1.37, 95% CI 1.26 to 1.50) or other oral hypoglycemic agent (OHA) 

monotherapy (HR 1.16, 95% CI 1.04 to 1.28). The relative rates of LA or serious infection were 

also reported by renal function, using other OHAs as the referent. Metformin compared with

other OHAs showed lower rates of LA or serious infection in patients with eGFR 

≥60ml/min/1.73m2 (HR 0.91, 95% CI 0.84 to 0.98) and eGFR 45 to <60 (HR 0.85, 95% CI 0.74 

to 0.97) and no increased risk in patients with eGFR 30 to 45 (HR 0.98, 95% CI 0.79 to 1.21). 

The second study, also with moderate ROB, compared risk of LA among metformin users with 

never users of a noninsulin antidiabetic drug (NIAD).34 Over a mean follow-up of 4.3 years, the 

overall incidence rate of LA or elevated lactate concentrations (>5mmol/L) was 7.4 events per 

100,000 person-years among metformin users compared with 2.2 events per 100,000 personyears among NIAD users. Current metformin users had an increased, albeit not statistically 

significant, risk of LA or elevated lactate compared with NIAD users who had never used 

metformin, HR 4.03 (0.97 to 16.8). Subgroup analysis by renal function category (eGFR ≥ 60, 45 

to 59, 30 to 44, <30ml/min/1.73m2

) revealed an adjusted HR of composite LA outcome in 

metformin users compared with never users of 2.87 (95% CI 0.67 to 12.3), 6.06 (1.37 to 27.1), 
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5.47 (1.05 to 28.5), 25.7 (3.57 to 185), respectively. The different comparative rates of LA 

reported in these 2 studies may be related to outcome assessment, with the former study using 

diagnosis codes for acidosis, serious infection, shock or acute renal failure as proxies for LA, 

while the latter study used both diagnosis codes for LA and serum lactate levels to define the 

outcome of interest. 

Congestive Heart Failure

A study with moderate ROB evaluated the safety of metformin use among 10,920 heart failure 

patients (diagnosed by ICD 9 code) with T2D.25 Danish individuals taking various permutations 

of metformin, sulfonylurea, and or insulin therapy were followed for a median of 844 days, 

during which there were no documented reports of LA across all therapies. A prospective study 

with low ROB from Spain evaluated the effect of newly initiated metformin therapy in 

individuals with new-onset heart failure (based on Framingham criteria) and previously unknown 

T2D.35 The authors matched 592 heart failure patients with T2D not treated with metformin to 

592 patients who began metformin therapy. Over a median follow-up of 56.7 months, there were 

no cases of LA in either group. 

Chronic Liver Disease

A single study with low ROB from the United States evaluated the risk of metformin use in 

individuals with cirrhosis and T2D.38 Individuals on metformin at the time of cirrhosis diagnosis 

were categorized into those who continued on metformin therapy and those who discontinued 

metformin use. The majority (172, 68.8%) of individuals continued metformin therapy whereas 

78 (31.2%) discontinued use following a cirrhosis diagnosis. The median duration of metformin 

use in those who continued therapy was 26.8 months. Over a median survival of 11.8 years in 

those who continued metformin and 5.6 years in those who discontinued metformin, there were 

no reported cases of LA in either group (Table 4). Characteristics of studies evaluating the rate of 

LA with metformin use compared with other hypoglycemic medications.

Table 4. Rate of LA with Metformin Use Compared with Other Hypoglycemic Medications

Study

Country

Precaution

Analysis Sample Comparison Outcome

Ekstrom, 201240

Sweden

CKD: eGFR category 

(30 to <45, 45 to <60, 

≥60ml/min/1.73m2

) 

n = 51,675

Metformin versus

use of other oral 

antidiabetic agent 

(dose NR)

LA or serious infection: lower in 

eGFR 60ml/min and 45 to <60; 

no increase in eGFR 30 to 45

over a mean follow-up of 3.9 

years.

Eppenga, 201434

Great Britain

CKD: eGFR category 

>60, 45-59, 30-44, <30

n = 258,539

Metformin versus 

never use of 

metformin but 

current use of other 

NIAD

LA: 7.4/100,000 vs 2.2/100,00 

persons-years, p = NS, over 

mean follow-up of 4.3 years

Andersson, 201025

Denmark

CHF: First CHF 

hospitalization based 

on diagnostic codes

n = 10,920

Multiple comparator 

arms

LA : none in any group over a 

median follow-up of 844 days 

Romero, 201335

Spain

CHF: Framingham 

criteria

n = 1,184

Metformin versus no 

metformin use

LA: none reported over a median 

56.9 months follow-up
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Study

Country

Precaution

Analysis Sample Comparison Outcome

Zhang, 201438

US

CLD: Biopsy-proven 

cirrhosis with additional 

clinical evaluation

N = 250

Continued metformin 

versus discontinued 

metformin use

LA: none in either group over 5-

10 years follow-up

Abbreviations: CHF = congestive heart failure; CKD = chronic kidney disease; eGFR = estimated glomerular 

filtration rate; ICD = International Classification of Diseases; LA = lactic acidosis; ROB = risk of bias

Quality of Evidence for Key Question 1

Studies examining the rate of LA among metformin users with a precaution used observational 

designs and were judged high ROB. Frequent quality issues were incomplete adjustment for 

difference in baseline characteristics, unequal follow-up, and outcomes assessed with knowledge 

of the intervention or with measures that included events other than LA. With the exception of 

unequal baseline characteristics, similar issues were observed for studies comparing rates of LA

in metformin users versus nonusers. Due to significant heterogeneity across studies and 

contraindications, meta-analysis was not performed. 

Summary of Findings

Based on our qualitative synthesis of observational evidence, the risk of LA with metformin use 

among individuals with a precaution appears to be low. Risk of LA with metformin use does not 

appear to be higher than the risk of LA with other hypoglycemic medications. In patients with 

CKD, the risk of LA with metformin use appears to be highest in individuals with eGFR 

<30ml/min/1.73m2. In limited studies of patients with CHF, there were no cases of LA with 

metformin use. A single study evaluating the rate of LA with metformin use in cirrhosis reported 

no cases of LA. Reports on the risk of LA among older adults are conflicting.
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KEY QUESTION 2: For patients with type 2 diabetes and an apparent 

contraindication/precaution to metformin use, what are the potential 

benefits and harms (other than lactic acidosis) of continued treatment 

with metformin?

Key Findings

Among patients with medically treated T2D and CKD, metformin use is associated with a 

significantly lower risk of all-cause mortality when compared with non-metformin 

treatment (high heterogeneity present on meta-analysis); limited evidence was identified 

for major adverse cardiovascular events (MACE).

Among patients with medically treated T2D and CHF, metformin use is associated with a 

significantly lower risk of all-cause mortality and heart failure readmission when 

compared with non-metformin treatment, but risk of cardiovascular mortality did not 

differ (moderate-to-high heterogeneity present on meta-analyses).

Among patients with medically treated T2D and CLD with cirrhosis, limited evidence 

suggests that a lower risk of all-cause mortality may be associated with metformin use 

when compared with non-metformin treatment.

Among patients with medically treated T2D and older age (generally age 65 years), 

limited evidence suggests that, compared with non-metformin treatment, metformin may 

be associated with a lower risk of all-cause mortality and some MACE outcomes.

No evidence was identified regarding the effects of metformin on glycemic control, lipid 

control, weight, hypoglycemia, or vitamin B12 deficiency among patients with medically

treated T2D and CKD, CHF, or CLD; additionally, no evidence was identified for MACE 

in CLD.

While limited evidence suggests that progressively lower estimated glomerular filtration 

rate (eGFR) may diminish the mortality benefit associated with metformin use, the 

impact of CHF severity, CLD severity, and increasing older age on the effects of 

metformin is unclear.

For KQ 2, we present the detailed results ordered by precaution (CKD, CHF, CLD, and older 

age) and, within precaution, by major outcomes. Details on study characteristics are in Appendix 

F. Further details on results for older adults by study design are in Appendix G.

Chronic Kidney Disease

Five studies – all of which used observational cohort designs (4 retrospective,40-43 one 

prospective44) – evaluated the effect of metformin on KQ2 outcomes in patients with T2D and 

CKD. Two studies were conducted in the United States,41,42 2 in Europe (Sweden and UK),40,43

and one across multiple continents.44 One study was conducted specifically among Veterans 

using VA data.41 Three studies reported government funding only,40-42 one reported industry 

funding only,43 and one reported both industry and foundation funding.44
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All-cause Mortality

All 5 studies evaluated the effect of metformin on all-cause mortality compared with nonmetformin treatments in adults with T2D and CKD. Two studies had low risk of bias (ROB)41,43

and 3 had moderate ROB.40,42,44 In all, these studies involved 33,442 patients with CKD; while 

the entire population had CKD in 3 studies,40-42 we examined a CKD subgroup in the remaining 

2.43,44 Individual study sample sizes ranged from 1,246 to 11,481 patients with CKD. Mean 

follow-up periods ranged from one to 3.9 years. 

The mean/median age of study participants ranged from approximately 65 to 76 years. CKD 

definitions varied between studies, with 3 reporting eGFR-based definitions40,41,44 and 2 using 

serum creatinine-based definitions.42,43 Two studies provided outcomes by CKD severity 

subcategory,40,44 while the other studies did not provide data on CKD severity. Only one study 

reported the population’s median metformin dose (1100mg to 1900mg daily in different 

subgroups).40 Mortality was defined using medical record or administrative data for the 4 

retrospective studies, while the single prospective study determined mortality on 2-year followup assessment.44 All studies performed statistical adjustment based on multiple baseline 

population differences between metformin users and nonusers; 2 studies utilized propensity score 

matching.41,44

Individually, most studies indicated that metformin use was associated with lower mortality 

when compared with non-metformin treatment. These studies were deemed to have sufficient 

conceptual homogeneity to perform quantitative synthesis. Based on meta-analysis of all patients 

(Figure 2), there was a statistically significant summary hazard ratio (HR) for mortality favoring 

metformin (HR 0.78, 95% CI 0.63 to 0.96). Significant statistical heterogeneity was present. 

Two studies reported mortality by CKD severity subcategory and suggested that patients with 

eGFR <45 mL/min/1.73m2 experienced less benefit with metformin (Figure 2).

40 A sensitivity 

analysis that excluded a subgroup of 573 patients specifically identified by one study as having 

eGFR <30 mL/min/1.73m2 produced similar findings to the overall meta-analysis.

44
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Figure 2. Meta-analysis of All-cause Mortality with Use of Metformin Versus Nonmetformin Treatment Among Patients with CKDa,b

a Studies on the forest plot are ordered by increasing CKD severity. b Eckstrom, 2012, and Roussel, 2010, stratified their respective populations by eGFR; these eGFR categories are 

presented separately for these studies.

Major Adverse Cardiovascular Events

Two studies evaluated the effect of metformin on MACE versus non-metformin treatments in 

adults with T2D and CKD, both of which had moderate ROB.40,42 In all, these studies reported 

MACE outcomes in 14,408 patients with CKD. One study included a subgroup of 8,549 patients 

with CKD (mean age approximately 65 years) followed for a mean of 3.9 years,40 while the other 

included a subgroup of 5,859 patients with CKD (mean age approximately 76 years) followed 

for a mean of one year.42 

One study used an eGFR-based definition of CKD (with reporting of CKD subcategories),40

while the other used a serum creatinine-based definition.42 Only one study reported the 

population’s median metformin dose (1100mg to 1900mg daily in different subgroups).40 Both 

studies utilized different MACE outcomes; one used administrative data to identify MACEassociated diagnosis codes,40 and the other used administrative data to identify readmission for 

heart failure.42 Both studies performed statistical adjustment based on multiple baseline 

population differences between metformin users and nonusers. 

Given the low number of studies and differences in MACE outcomes presented, quantitative 

synthesis was not attempted. One study found no statistically significant difference in MACEassociated diagnoses between metformin users and nonusers with eGFR 45 to <60 (n = 6655, HR 

0.94, 95% CI 0.84 to 1.05) or 30 to <45 (n = 1894, HR 1.00, 95% CI 0.83 to 1.19).40 The other 

study found that metformin use was significantly associated with slightly lower CHF 

readmission (n = 5859, HR 0.91, 95% CI 0.84-0.99). 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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Other Outcomes

No studies were identified that evaluated the effect of metformin on other outcomes of interest 

(glycemic control, lipid control, hypoglycemia, weight gain, B12 deficiency) in adults with T2D 

and CKD.

Congestive Heart Failure

Eleven studies—all of which used observational designs (8 retrospective cohort,25,26,41,42,45-48 2 

prospective cohort,35,44 and one nested case-control27)—evaluated the effect of metformin on KQ 

2 outcomes in patients with T2D and CHF. Six studies were conducted in the United 

States,27,41,42,46-48 3 in Europe,25,35,45 one in Canada,26 and one across multiple continents.44 One 

study was conducted specifically among Veterans using VHA data.41 Six studies reported 

government funding only,25,35,41,42,46,48 one reported foundation funding only,45 2 reported both 

government and foundation funding,26,47 one reported both industry and foundation funding,44

and one did not report funding.27

All-cause Mortality

All 11 studies evaluated the effect of metformin on all-cause mortality versus non-metformin 

treatment in adults with T2D and CHF. Two studies had low ROB35,41 and the others had 

moderate ROB. In all, these studies involved 35,410 patients with CHF; while the entire 

population had CHF in 9 studies,25-27,35,41,42,45-47 we examined a CHF subgroup in the remaining 

2.44,48 Individual study sample sizes ranged from 346 to 13,930 patients with CHF. Mean followup periods ranged from one to 4.7 years. 

The mean/median age of study participants ranged from approximately 55 to 77 years. CHF 

definitions varied widely between studies, with most using diagnosis codes. CHF severity was 

likewise reported variably, with 4 studies reporting left ventricular ejection fraction-based 

definitions,35,41,42,47 2 reporting New York Heart Association-based definitions (both of which 

also reported left ventricular ejection fraction data),35,47 and 2 reporting other clinical definitions 

(eg, “decompensated heart failure” or “moderate-to-severe heart failure”).25,46 The remaining 5 

studies did not report CHF severity.26,27,44,45,48 No studies reported mortality for specific CHF 

severity subgroups. No studies reported their population’s median metformin dose. Mortality 

was defined using medical record or administrative data for 9 studies.25,27,35,41,42,45-48 One 

prospective study determined mortality on 2-year follow-up assessment44 and one study did not 

report how mortality was defined.26 All studies performed statistical adjustment based on 

multiple baseline population differences between metformin users and nonusers; 4 studies 

utilized propensity score matching.26,27,41,44

These studies were deemed to have sufficient conceptual homogeneity to perform quantitative 

synthesis. Based on meta-analysis of all patients, there was a statistically significant summary 

HR for mortality favoring metformin (Figure 3). Moderate heterogeneity was present. Two 

studies reported mortality by CHF subcategory. One reported mortality by LVEF category and 

found no difference with metformin use in subgroups with moderate CHF (LVEF 30% to 39%; 

HR 0.87; 95% CI 0.67 to 1.13) or severe CHF (LVEF <30%; HR 0.87; 95% CI 0.69 to 1.08).

42

The other included only patients with LVEF <40% and found no mortality difference with 

metformin use (HR 0.79; 95% CI 0.36 to 1.71).

47
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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Figure 3. Meta-analysis of All-cause Mortality with Use of Metformin Versus Nonmetformin Treatment Among Patients with CHFa

a Studies on the forest plot are ordered chronologically. 

Major Adverse Cardiovascular Events

Six studies evaluated the effect of metformin on MACE outcomes versus non-metformin 

treatments in adults with T2D and CHF.25-27,35,41,42 Two studies had low ROB35,41 and the others 

had moderate ROB. In all, these studies involved 26,510 CHF patients with CHF readmission as 

an outcome and 6,468 with cardiovascular mortality as an outcome; also, in all 6 studies, the 

entire population had CHF. Individual study sample sizes ranged from 981 to 13,390 patients 

with CHF. Mean follow-up periods ranged from one to 4.7 years. 

The mean/median age of study participants ranged from approximately 55 to 77 years. Most 

studies used diagnosis codes to define CHF. CHF severity was reported variably, with 3 studies 

reporting left ventricular ejection fraction-based definitions,35,41,42 one reporting a New York 

Heart Association-based definition (also reported left ventricular ejection fraction data),35 and 

one reporting a clinical definitions ( “decompensated heart failure”).25 The remaining 2 studies 

did not report CHF severity.26,27 No studies reported MACE outcomes for specific CHF severity 

subgroups. No studies reported their population’s median metformin dose. Two MACE 

outcomes were reported by these studies: CHF readmission and cardiovascular mortality. CHF 

readmission was reported by 4 studies,27,35,41,42 all of which defined this outcome using medical 

record or administrative data. Cardiovascular mortality was reported by 3 studies, 2 of which 

defined this outcome using medical record or administrative data,25,35 and one of which did not 

report how the outcome was defined.26 All studies performed statistical adjustment based on 

multiple baseline population differences between metformin users and nonusers; 3 studies 

utilized propensity score matching.26,27,41 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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These studies were deemed to have sufficient conceptual homogeneity to perform quantitative 

synthesis; we performed separate meta-analyses for each MACE outcome. Based on metaanalysis of available patients, there was a small but statistically significant summary HR for CHF 

readmission favoring metformin (Figure 4) though high heterogeneity was present. The summary 

HR for cardiovascular mortality also favored metformin (Figure 5) but was not statistically 

significant; high heterogeneity was present. 

Figure 4. Meta-analysis of CHF Readmission with Use of Metformin Versus Nonmetformin Treatment Among Patients with CHFa

Abbreviations: CI=confidence interval; CHF=congestive heart failure; HR=hazard ratio; ROB=risk of bias

a Studies on the forest plot are ordered chronologically.

Figure 5. Meta-analysis of Cardiovascular Mortality with Use of Metformin Versus Nonmetformin Treatment Among Patients with CHFa

a Studies on the forest plot are ordered chronologically.

Other Outcomes

No studies were identified that evaluated the effect of metformin on other outcomes of interest 

(glycemic control, lipid control, hypoglycemia, weight gain, B12 deficiency) in adults with T2D 

and CHF. 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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Chronic Liver Disease

Three studies, 2 of which used retrospective cohort designs38,49 and one of which used a 

prospective cohort design,50 evaluated the effect of metformin on KQ 2 outcomes in patients 

with T2D and CLD (Table 5). Two studies were conducted in Europe49,50 and one in the United 

States.38 No studies specifically addressed Veterans. One study reported government funding 

only,49 one reported both government and foundation funding,38 and one did not report funding.50 

All-cause Mortality

All 3 studies evaluated the effect of metformin on all-cause mortality versus non-metformin 

treatment in adults with T2D and CLD. One study had low ROB38 and one had moderate ROB.49

The other study50 was well-designed in general but was considered to have high ROB with 

regard to the outcome of all-cause mortality because only unadjusted event rates could be 

derived from the information presented in the article. In all, these studies involved 432 patients 

with CLD; in all 3 studies, the entire population had CLD. Individual study sample sizes ranged 

from 82 to 250 patients. Median follow-up time ranged from about 4.5 to 5.7 years. 

All studies focused on patients with CLD with known cirrhosis, as defined by histologic criteria 

with other adjunctive clinical criteria (ultrasound, biochemical parameters). No studies reported 

the population’s median metformin dose. Mortality was defined based on medical record or 

administrative data in the 2 retrospective studies,38,49 and by every-6-month assessment in the 

prospective study.50 All studies performed statistical adjustment based on baseline population 

differences between metformin users and nonusers for their primary analyses; however, as 

above, only all-cause mortality event rates were provided in 2 studies, so incidence was 

unadjusted.49,50 

Given the low number of studies and differences in study quality with regard to the outcome of 

all-cause mortality, quantitative synthesis was not attempted. The study with low ROB found a 

significantly longer survival associated with metformin therapy (n = 250, HR 0.43, 95% CI 0.24 

to 0.78), which was observed regardless of cirrhosis severity (Child-Pugh class A: HR 0.47, 95% 

CI 0.27 to 0.82; class B/C: HR 0.46, 95% CI 0.21 to 0.98).38 Of note, on additional post-hoc 

subgroup analysis, the beneficial effect of metformin on survival was seen only among patients 

with cirrhosis secondary to nonalcoholic steatohepatitis (n = 142, HR 0.33, 95% CI 0.17 to 0.63); 

no statistically significant differences were seen among the relatively small groups of patients 

with cirrhosis related to alcohol, hepatitis C virus, or hepatitis B virus. 

The study with moderate ROB found a trend toward a lower all-cause mortality rate among 

cirrhotic patients taking metformin compared with nonusers of metformin (n = 82, 7.3% [3/41] 

versus 17.1% [7/41], p = NR).49 In the study with high ROB, there was likewise an apparently 

lower all-cause mortality rate among patients taking metformin compared with nonusers (n = 

100, 7.7% [2/26] versus 48.6% [36/74], p = NR); however, as above, baseline population 

differences were present without adjustment.50

Table 5. Effects of Metformin on Mortality in Patients with CLD

Study Design Comparison Outcome (Adjusted analysis)

Ampuero, 201249 Retrospective 

cohort

Metformin 

versus no 

Rate of all-cause mortality: 7.3% vs 17.1%,

p = NR
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n = 82 metformin

Nkontchou, 201150 Prospective 

cohort

n = 100

Metformin 

versus no 

metformin 

Rate of all-cause mortality: 7.7% vs 48.6%, 

p = NR

Zhang, 201438 Retrospective 

cohort

n = 250

Metformin 

continuation 

versus 

discontinuation

Survival: 11.8 versus 5.6 years (p<0.0001), 

HR 0.43 (95% CI 0.27 to 0.82, p = 0.005)

Survival subgroup analysis:

Child-Pugh class A: HR 0.47 (95% CI 0.27 

to 0.82) class B/C: HR 0.46 (95% CI 0.21 to 

0.98)

Other Outcomes

No studies were identified that evaluated the effect of metformin on other outcomes of interest 

(MACE, glycemic control, lipid control, hypoglycemia, weight gain, B12 deficiency) in adults 

with T2D and CLD. 

Older Adults

Fourteen studies evaluated the effect of metformin in older adults (7 RCTs,51-57 7 observational58-

64). Most studies were conducted in North America, with the remaining conducted in Europe or 

across multiple continents. Three large observational studies were conducted using VA 

data.58,62,63 Results are organized by major outcomes, and within outcomes, by RCT then 

observational studies. 

All-cause Mortality and Major Adverse Cardiovascular Events

A single large RCT evaluated the effects of metformin compared to other usual care treatments 

in adults with T2D who were suboptimally controlled on diet or sulfonylurea.52 This 1-year trial 

with moderate ROB randomized 7,200 adults to metformin and 1,200 to non-metformin 

treatment as directed by their physician. Outcomes were reported in the subgroups <65 years of 

age and 65 years of age. In the older subgroup (n = 3,084), all-cause mortality did not differ 

between metformin and usual care (2.4% vs 2.1%, p = 0.878). The rate of emergent cardiac 

disorders was identical between groups (5.6%). 

Three retrospective cohort studies evaluated the effects of metformin on all-cause mortality58,63,64

and one reported effects on a composite measure of acute MI, stroke, or death.62 All 4 studies 

showed lower mortality or a composite of major cardiovascular event and mortality in older 

adults treated with metformin compared with a sulfonylurea. However, the study conducted in a 

cohort of older Veterans63 found no effect in those who were frail as defined by an ICD-9 code 

for anemia, fluid electrolyte imbalance, fall, fracture, head injury coagulopathy, or weight loss 

(Table 6). Rosiglitazone monotherapy (but not combination therapy) was associated with 

increased CHF (HR 1.32; 95% CI 1.07, 1.63). 

Table 6. Effects of Metformin on Mortality or MACE in Older Adults

Study Design Comparison Outcome (Adjusted Analysis)

Bannister, 201458 Retrospective 

cohort

n = 90,463

Sulfonylurea versus 

metformin

Survival

Age 64-71: Survival time ratio 0.55 (95% 

CI 0.47 to 0.65)
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Age >88: Survival time ratio 0.58 (95% CI 

0.54 to 0.63)

Cryer, 200552 RCT

n = 7,200

Usual care versus 

metformin

Mortality in subgroup age 65 years: 2.1% 

vs 2.4%, p = 0.88

Roumie, 201262 Retrospective 

cohort

n = 253,690

Sulfonylurea versus 

metformin

MACE or mortality 

HR 1.18 (95% CI 1.09, 1.28)

MACE: HR 1.13 (95% CI 1.03, 1.24)

Tzoulaki, 200964 Retrospective 

cohort

n = 91,521

Second- generation 

sulfonylurea versus 

metformin

Rosiglitazone versus 

metformin

Subgroup age 65 years:

Mortality: HR 1.35 (95% CI 1.28, 1.42)

Myocardial infarction: HR 1.22 (95% CI

1.10, 1.35)

CHF: HR 1.18 (95% CI 1.10, 1.26)

No difference in mortality or myocardial 

infarction. Increased CHF (HR 1.32, 

95%CI 1.07, 1.63) with monotherapy but 

not in combination with other hypoglycemic 

drugs

Wang, 201463 Retrospective 

cohort

n = 2,415

Metformin versus 

sulfonylurea

Mortality

With frailty: HR 0.92 (95% CI 0.90, 1.31)

Without frailty: HR 0.69 (95% CI 0.60, 

0.79)
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Glycemic Control

Six RCTs (1144 patients) evaluated the effects of metformin on glycemic control.51,53-57 One trial 

enrolled patients >70 years of age;54 all other trials enrolled or analyzed subgroups of patients 

≥65 years of age. In 4 trials, eligible patients had suboptimal glycemic control on a sulfonylurea 

or metformin monotherapy.51,54-56 All but one trial specifically excluded patients with renal 

disease, and the majority excluded patients with CLD or CHF.55 In 4 trials, metformin 

monotherapy was compared with a sulfonylurea51,53,56 or DPP-4 inhibitor monotherapy.57 One 2-

arm trial54 and 3 multi-arm trials51,53,56 included a comparison of metformin plus sulfonylurea 

with sulfonylurea alone. One trial compared a combination of metformin plus a sulfonylurea 

with pioglitazone plus a sulfonylurea.55 Outcomes were assessed at a median of 22 weeks (range: 

16 weeks to 18 months). ROB was assessed as low in 5 trials and high in 1 trial, but in 4 studies, 

results were based on post-hoc subgroup analyses. Appendix F has details on the study 

characteristics.

Effects of treatment were analyzed differently across trials, and statistical tests were not always 

reported for between group comparisons (Table 7). However, the differences between metformin 

and sulfonylurea or DDP-4 inhibitor monotherapy were uniformly small (HbA1c difference 

0.3% between metformin and comparator groups). Metformin plus a sulfonylurea compared 

with metformin plus pioglitazone yielded similar reductions in A1c. When metformin was 

combined with a sulfonylurea and compared to treatment with a sulfonylurea alone,51,53,54,56 the 

combination was associated with greater reductions in A1c in 2 of the 4 trials (range: -0.7 to -1.8 

combination versus +0.2 to -1.2 for sulfonylurea monotherapy). 

One study used a retrospective cohort design to evaluate the effects of metformin on glycemic 

control in 2,107 Veterans.60 Outcomes were adjusted for multiple demographic and clinical 

covariates. Twelve-month A1c was similar in metformin and sulfonylurea users overall; no 

interaction effects were found by age group (<65, 65-75, and >75 years of age). 

Table 7. Effects of Metformin on A1c in Older Adults—RCTs

Study Precaution

Analysis Sample

Intervention (average dose): Effect on A1ca

Comparator (average dose): Effect on A1c

Blonde, 

200251 Age ≥65n = 65, subgroup

Metformin (1840mg): A1c change +0.2%

Glibenclamide (20mg): A1c change -0.1%

Metformin (1759mg) + Glibenclamide (8.8mg): A1c change -1.5%

Metformin (1744mg) + Glibenclamide (17.4mg): A1c change -1.8%

Garber, 

200253

Age ≥65

n = 74, subgroup

Metformin (1324mg): A1c change -0.9%

Glibenclamide (5.4mg): A1c change -1.2%

Metformin (568mg) + Glibenclamide (2.8mg): A1c change -1.5%

Metformin (840mg) + Glibenclamide (4.2mg): A1c change -1.3%

Gregorio, 

199954

Age >70 

n = 174, whole 

sample

Metformin (1518mg) + Sulfonylurea: A1c mean 8.54 (SE 0.12)

Glibenclamide (13.2mg) or Glycoside (214.7mg): A1c mean 8.58 

(SE 0.12)

Hanefeld, 

200455 Age ≥65n = 169, 

subgroup

Metformin + Sulfonylurea (NR): A1c change -1.46 (SE 0.08)

Pioglitazone + Sulfonylurea (NR): A1c change -1.41 (SE 0.09)
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Study Precaution

Analysis Sample

Intervention (average dose): Effect on A1ca

Comparator (average dose): Effect on A1c

Marre, 

200256

Age ≥65

n = 59, subgroup

Metformin (1660mg): A1c change -0.1%

Glibenclamide (13.4mg): A1c change +0.2%

Metformin (1225mg) + Glibenclamide (6.1mg): A1c change -1.3%

Metformin (170mg)+ Glibenclamide (11.7mg): A1c change -0.7%

Schweizer, 

200957 Age >65n = 335, whole 

sample

Metformin (1500mg): A1c change -0.75%

Vildagliptin (100mg): A1c change -0.64%

a Average dose is reported for the sample overall; dose for older adult subgroup is not known.

Cholesterol and Weight

Two trials (386 patients) reported the effects of metformin on cholesterol and weight in older 

adults.54,55 A study with low ROB conducted a post-hoc analysis of 212 adults >65 years of age 

with inadequate control on a sulfonylurea who were randomized to pioglitazone or metformin.55

At 52 weeks, the change in LDL cholesterol did not differ significantly between groups, but 

HDL increased more in the pioglitazone group (pioglitazone 16.77 vs metformin 7.85, p<0.05). 

More patients in the pioglitazone group gained weight than in the metformin group (4.8% vs 1%, 

p = NR). One trial with high ROB that enrolled 174 patients >70 years of age compared the 

addition of metformin to increased doses of a sulfonylurea in patients with A1c 95 on 

sulfonylurea monotherapy.54 At 18-month follow-up, LDL decreased significantly and HDL 

increased significantly for the metformin group. However, treatment differences between groups 

were not reported. Change in weight differed by less than 1kg between the 2 groups. 

Adverse Effects: Hypoglycemia, B12

Five RCTs (742 patients)51,53,55-57 and a nested case-control study59 reported rates of 

hypoglycemia (Table 8). Definitions of hypoglycemia varied, with some studies requiring fasting 

plasma glucose below 50mg/dl to 60mg/dl and other studies relying on symptoms. 

Hypoglycemic events in the RCTs were low except in one study that did not report the definition 

used for hypoglycemic episodes.55 Hypoglycemic events were lower for metformin compared 

with a sulfonylurea in one of 3 studies,53 and did not differ in the single trial comparing 

metformin with vildagliptin.

55 In a trial comparing metformin used in combination with a 

sulfonylurea versus in combination with pioglitazone, hypoglycemic events did not differ 

between metformin and comparators, but 95% confidence intervals are extremely broad because 

of the small number of trials and patients enrolled.57 
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Table 8. Effects of Metformin on Hypoglycemic Events in Older Adults

Study Design Comparison Hypoglycemic Outcomesa

Blonde, 200251 RCT

n = 65

Metformin vs 

sulfonylurea

OR = 2.82 (95% CI, 0.11 to 71.84)*

Bodmer, 200959 Nested case 

control

n = 7,753

Sulfonylurea vs 

metformin

OR for age 65 years = 3.30 (95% CI 

2.18 to 5.00)

Garber, 200253 RCT

n = 74

Metformin vs 

sulfonylurea 

OR 0.08 (95% CI 0.01 to 0.68)*

Hanefeld, 200455 RCT

n = 212

Metformin vs 

vildagliptin

OR 1.24 (95% CI, 0.57 to 2.73)*

Marre, 200256 RCT

n = 59

Metformin vs 

sulfonylurea

OR 0.24 (95% CI, 0.01 to 5.17)*

Schweizer, 200957 RCT

n = 322

Metformin + 

sulfonylurea versus 

metformin + 

pioglitazone

OR 5.12 (95% CI 0.24 to 107.51)*

a OR and 95% CI calculated from data reported. 

The nested case-control study with low ROB used data from the UK-based General Practice 

Research Database to compare rates of hypoglycemia in current sulfonylurea users with current 

metformin users.59 Overall, 2,025 case subjects with hypoglycemia were compared with 7,728 

matched-control subjects; stratified analyses for patients <70 and 70 years of age were 

presented. The risk of hypoglycemia was elevated for sulfonylurea users in those <70 (OR 2.71; 

95% CI 2.04 to 3.61) and those 70 (OR 3.30; 95% CI 2.18 to 5.00). 

A single small, nonrandomized trial compared vitamin B12 (cobalamin) levels in 10 older adults 

assigned to metformin and 10 controls.59 Outcomes were assessed at 3 months’ follow-up. 

Patients assigned to metformin compared with the control group had a significant decrease in 

total cobalamin levels (-110pM vs -26pM).

Quality of Evidence for Key Question 2

Studies included for KQ 2 were mostly rated as moderate ROB, with some rated low ROB 

(Appendix F). Few studies were rated high ROB. Common quality concerns included (1) 

incomplete accounting for differences in baseline characteristics and confounding by indication, 

though some studies did use propensity score matching; (2) limited assessment of metformin use 

throughout the study period (eg, assessment at baseline only without accounting for subsequent 

metformin discontinuation in the exposed group or initiation in the unexposed group), though 

some studies did analyze metformin exposure status in ‘intervals’ to account for this concern; (3) 

incomplete assessment and description of attrition within the study populations; and (4) 

unblinded outcome assessment. These factors may have contributed to the heterogeneity in our 

qualitative and quantitative syntheses. 

Summary of Findings

Based on our quantitative syntheses of observational evidence, metformin use is associated with 

a lower risk of all-cause mortality when compared with non-metformin treatment among patients 

with medically treated T2D and CKD. High heterogeneity was present on meta-analysis, but 

appeared to be related to variance in the magnitude of effects that consistently favored
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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metformin. The impact of CKD severity on the apparently beneficial effect of metformin on allcause mortality is not completely clear based on available data, but limited evidence may 

indicate less benefit with progressively lower eGFR. Qualitative synthesis of limited 

observational evidence shows that metformin use may be associated with a lower risk of CHF 

readmission when compared with nonuse among patients with medically treated T2D and CKD, 

and with a similar risk of MACE-associated diagnoses. 

Based on our quantitative syntheses of observational evidence, metformin use is associated with 

a lower risk of all-cause mortality when compared with non-metformin treatment among patients 

with medically treated T2D and CHF. Moderate heterogeneity was present on meta-analysis, but

appeared to be related to variance in the magnitude of effects that consistently favored

metformin. The impact of CHF severity on the apparently beneficial effect of metformin on allcause mortality is unclear. Based on our quantitative syntheses of observational evidence, 

metformin use is associated with a lower risk of CHF readmission when compared with nonuse 

among patients with medically treated T2D and CHF, though high heterogeneity was present. A 

quantitative synthesis of available data showed no difference in the risk of cardiovascular 

mortality with metformin use versus non-metformin treatment.

Limited evidence is available regarding all-cause mortality in CLD, but qualitative synthesis of 

available evidence suggests that metformin may be beneficial in this population. 

Data on the effects of metformin in older adults are limited, with most coming from subgroup 

analyses of randomized trials and in samples without coexisting CHF, CKD, or CLD. Qualitative 

synthesis of available data indicates that metformin use does not increase all-cause mortality or 

MACE relative to nonuse. Qualitative synthesis of available data suggests that metformin 

monotherapy provides similar reductions in HbA1c as sulfonylurea or vildagliptin monotherapy 

does. Qualitative synthesis of available data indicates that metformin use is not associated with 

higher rates of hypoglycemia than non-metformin treatment.

No evidence was identified regarding the effects of metformin on glycemic control, lipid control, 

weight, hypoglycemia, or vitamin B12 deficiency among patients with medically treated T2D 

and CKD, CHF, or CLD; additionally, no evidence was identified for MACE in CLD. Likewise, 

the impact of CHF severity, CLD severity, and increasing older age on the effects of metformin 

use is unclear based on available evidence.
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SUMMARY AND DISCUSSION

This systematic review examined outcomes associated with metformin use in T2D populations 

with traditional contraindications or precautions to receiving metformin. In KQ 1 we assessed the 

incidence of LA with metformin use among patients with CKD, CHF, CLD, or older age (KQ 

1a); we also evaluated the comparative incidence of LA in these populations with use of 

metformin compared with other antidiabetic agents (KQ 1b). We focused on data published since 

2009, when Salpeter et al last updated their Cochrane review of LA with metformin use.16

Consistent with prior reviews,5 we found that metformin use is associated with an overall low 

risk of LA among individuals with traditional contraindications or precautions. Identified studies 

did suggest that patients with CKD may experience a slightly higher rate of LA while using 

metformin when compared with general diabetes populations; this risk appears highest in 

individuals with eGFR <30 mL/min/1.73m2

. We identified no new cases of metforminassociated LA for patients with CHF or CLD and found no data to suggest higher rates of LA 

with metformin use among older adults. Based on limited available evidence, the comparative 

risk of LA associated with metformin use among patients with CKD, CHF, or CLD does not 

appear higher than the risk with use of other hypoglycemic medications. We found no 

comparative studies examining LA in older adults.

In KQ 2 we examined the incidence of other key outcomes with use of metformin compared with 

other diabetes medications among patients with T2D and CKD, CHF, CLD, or older age. In

patients with T2D and CKD—including some with eGFR down to 30 mL/min—we found that 

metformin is associated with a lower risk of all-cause mortality compared with non-metformin 

therapies. In CHF, use of metformin is also associated with a lower risk of all-cause mortality 

compared with non-metformin therapies. Although data regarding all-cause mortality in CLD

and older age were limited, we found no evidence for an association between metformin use and 

increased all-cause mortality among patients with these precautions. While relatively few studies 

addressed MACE, metformin appears to be associated with lower rates of CHF readmission 

among patients with CHF; associations between metformin use and other MACE outcomes are 

unclear in other populations of interest. Also based on limited evidence, we found no clear 

association between metformin use and other outcomes of interest (glycemic control, lipid 

control, weight, hypoglycemia, or vitamin B12 deficiency) in T2D populations with historical 

contraindications or precautions to receiving metformin. 

Overall, data from general diabetes populations has established metformin as effective, unlikely 

to cause hypoglycemia or weight gain, and possibly associated with reduced cardiovascular 

events and reduced mortality1,65,66; although we found limited data in some areas, there is no 

evidence to suggest that metformin’s positive associations do not hold true in most populations 

with historical restrictions to metformin use.

STRENGTH OF EVIDENCE

In Table 9, we summarize the strength of evidence (SOE) for the effects of metformin use on the 

risk of LA. Using data from 209 RCTs, a prior Cochrane review identified no cases of LA; 

however, these trials did not recruit individuals with the precautions of interest. We identified 5 

observational studies reporting LA in patient using metformin compared to non-metformin users.

For cases of CKD, findings were inconsistent, but suggest that rates of LA in patients with CKD 

may be higher than metformin users overall. For CHF and CLD, there were no cases of LA.
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Table 9. Strength of Evidence for Effects of Metformin Use Versus Non-Metformin Use on 

Risk of LA (KQ 1b) 

Study Type # Studies 

(Patients) Findings SOERationale by Domain

LA in patients with CKD, CHF, or CLD

RCTsa 209 (NR) No cases, but trials did not recruit 

patients with contraindications or 

precautions

Low SOE

Moderate ROB, Consistent, 

Precise, Indirect

Observational 3 (12,354)

2 (310,214)

No cases in 2 cohort studies of 

patients with CHF and 1 study in 

patients with CLD. 

Inconsistent findings in 2 studies of 

patients with CKD

Insufficient SOE

Moderate ROB, Consistent, 

Imprecise, Direct

Insufficient SOE

Moderate ROB, Inconsistent, 

Imprecise, Indirect a Data are from the Cochrane review.16

In Table 10, we summarize the SOE for effects of metformin use on mortality and MACE. 

Because of the observational nature of the vast majority of studies examining this question, no 

firm conclusions may be drawn. However, in relation to all-cause mortality, in CKD, CHF and 

older adults, there is uniformly low SOE for fewer deaths among patients taking metformin. 

Further, in patients with CHF, there is also low SOE that metformin use may lower CHF 

readmission. There is insufficient evidence to determine whether this benefit may extend to 

cardiovascular mortality in patients with CHF. Specifically among older adults, there is low SOE 

that risk of myocardial infarction or stroke may be lower in patients taking metformin.

Table 10. Strength of Evidence for Effects of Metformin Use Versus Non-Metformin Use on 

Mortality and MACE (KQ 2) 

Outcome # Studies 

(Patients) Findings SOERationale by Domain

Patients with CKD

All-cause mortality 5 observational

(33,442)

HR 0.77 (95% CI 0.61, 0.97)

48 fewer deaths/1,000 (81 to 6 

fewer)

Low SOE

Moderate ROB, Inconsistent, 

Precise, Direct

Patients with CHF

All-cause mortality 11 observational

(35,410)

HR 0.78 (95% CI 0.71, 0.87)

48 fewer deaths per 1,000 (64 

to 29 fewer)

Low SOE

Moderate ROB, Consistent, 

Precise, Direct

Cardiovascular 

mortality

3 observational 

(6,468)

HR 0.77 (0.53, 1.12)

66 fewer deaths/1,000 (136 

fewer to 35 more)

Insufficient SOE

Moderate ROB, Consistent, 

Imprecise, Direct

CHF readmission 4 observational 

(26510)

HR 0.87 (95% CI 0.78, 0.97)

12 fewer readmissions per 

1,000 (20 to 3 fewer)

Low SOE

Low ROB, Consistent, 

Precise, Direct

Older Adults

All-cause mortality 1 RCT (3,084)

3 observational

(184,399)

Risk difference 0.3%, p = 0.88

Lower mortality except in frail 

older adults

Low SOE

Moderate ROB, Inconsistent, 

Precise, Direct
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

36

Outcome # Studies 

(Patients) Findings SOERationale by Domain

MACE 2 observational

(345,211) 

Lower composite myocardial 

infarction or stroke, lower MI, 

lower CHF versus sulfonylurea

Low SOE

Low ROB, Consistent, 

Precise, Direct

CLINICAL AND POLICY IMPLICATIONS

As the consensus first-line therapy for patients with T2D, metformin is the most widely 

prescribed diabetes drug in the world.67 Beyond its blood sugar–lowering effects, metformin is 

an appealing diabetes treatment option because it is safe, does not cause weight gain, and may be 

associated with improved long-term outcomes in general diabetes populations. 1,65,66 However, 

due to concerns about metformin-associated LA,

5 FDA labeling has traditionally specified renal 

impairment as a contraindication to metformin use, and acute or unstable CHF, hepatic 

impairment, and older age as precautions with metformin use. Recently, though, the FDA has 

relaxed restrictions on metformin prescribing. In April 2016, the FDA issued a statement 

supporting metformin initiation in patients with an eGFR >45 mL/min/1.73m2

 and continuation 

with appropriate monitoring in patients with an eGFR >30-45 mL/min/1.73m2.

11 

In the wake of these recent changes in FDA labeling, prescribing of metformin will undoubtedly 

increase. It has previously been estimated that one million additional patients would become 

eligible to use metformin in the United States alone if an eGFR cutoff of 30 mL/min/1.73m2

were implemented.68 It is therefore critically important that clinicians understand the full 

spectrum of risks and benefits associated with metformin use in populations with historical 

contraindications and precautions. This systematic review provides a comprehensive, up-to-date

evaluation of existing literature regarding multiple key outcomes associated with metformin use 

in T2D populations with traditional contraindications or precautions. Our findings support 

FDA’s recent actions and will directly inform clinicians’ prescribing practices for T2D patients

with traditional restrictions to receiving this medication. 

This analysis adds to existing knowledge about long-term outcomes of metformin use. Lamanna 

et al conducted a meta-analysis of randomized trials that suggested an association between 

metformin monotherapy and improved survival in general diabetes populations.1 In contrast, 

Palmer et al conducted a subsequent network meta-analysis that found no differences in 

mortality with different antihyperglycemic agents, including metformin.69 Our review differs 

fundamentally from these analyses in that we focused exclusively on diabetes populations with 

traditional metformin contraindications or precautions. Consequently, we included observational 

studies with longer follow-up periods, which are better suited to examining associations that 

require longer exposure to observe (eg, mortality). Our findings regarding CHF are consistent 

with those of Eurich et al,

18 who found that metformin is associated with reduced mortality in 

CHF; our analysis included 3 additional studies (n = 6,514),27,35,48 and excluded another that did 

not employ an active comparator.

70

In addition to informing clinician practice, this review may help inform the revision of 

prescribing guidelines within VA and professional societies. The 2016 American Diabetes 

Association guidelines already note that “accumulating observational data suggest that 

metformin may be safely continued down to glomerular filtration rate (GFR) of 45 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

37

mL/min/1.73m2 or even 30 mL/min/1.73 m2.”65 Our review, together with other reviews and the 

recent FDA labeling changes, may support strengthening this endorsement. 

STRENGTHS AND LIMITATIONS

This review’s strengths include a rigorous methodology, a thorough review of existing literature 

(which included a search for relevant RCT subgroup analyses), a comprehensive consideration of 

multiple traditional contraindications and precautions to metformin use, and an evaluation of 

multiple critical outcomes of interest. However, our approach has some limitations. First, 

because a Cochrane review described the risk of LA with metformin use based on literature 

published through 2009, we limited our KQ 1 literature search to articles published after this 

time. We limited our literature search for KQ 2 to articles published after 1994—the year FDA 

approved use of metformin in the United States. While it is possible we may not have captured 

relevant articles published before these dates, we searched the reference lists of prior published 

reviews and consulted content experts to ensure that no critical data were overlooked. 

Second, in order to assure relevance for our VA stakeholders, we limited our search to studies 

conducted in OECD countries. Although this approach may have excluded some potentially 

relevant articles from non-OECD countries, we feel that this decision enhances the applicability 

of our findings to our target population. Third, although we examined numerous relevant 

outcomes as informed by our VA stakeholders and technical expert panel, we did not examine all 

outcomes of potential interest. Because our primary interest was providing data to inform the 

safe prescribing of metformin in populations with traditional contraindications and precautions, 

we focused on outcomes we feel would be the most clinically relevant for prescribers. 

Beyond these limitations, the existing evidence base calls for additional caution in interpreting 

our findings. The studies we identified were primarily observational and, as such, come with 

potential limitations. First, although most included studies attempted to account for baseline 

differences between metformin and non-metformin populations through statistical adjustment 

(and in some cases, propensity score matching), confounding by indication remained a potential 

source for measured and unmeasured population differences. For example, most studies did not 

closely examine precaution severity; multiple studies included all patients whose eGFR fell 

below a certain cutoff or all patients with CHF diagnosis codes without accounting for ejection 

fraction. Unaccounted-for between-group differences in precaution severity could therefore have 

influenced our findings. Second, while some studies analyzed outcomes based on specific time 

intervals during which patients were or were not exposed to metformin, most studies defined 

metformin use at baseline only. As a result, some patients categorized as metformin-exposed 

could have discontinued metformin, and some unexposed patients could potentially have 

initiated treatment after baseline. Third, it is likely that different comparator therapies were 

utilized in different study populations. Most studies (including nearly all meta-analyzed studies) 

sought to compare T2D patients whose treatment regimens included metformin to those whose 

did not. As such, intervention and comparator patients alike may have used sulfonylureas, 

insulin, and other common diabetes medications, preventing assessment of outcomes with 

metformin versus specific comparators. We found few explicit comparisons to newer antidiabetic agents like DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT-2 inhibitors. Fourth, 

studies used different strategies for assessing outcomes of interest; this issue was particularly 

relevant for LA, where varying outcome assessment definitions contributed to markedly different 

incidence estimates. Fifth, the timing of outcome assessment varied between studies, and little 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

38

information was typically provided on attrition in study populations. All of these factors may 

have contributed to the heterogeneity on our qualitative and quantitative syntheses. However, 

because most meta-analyzed studies showed metformin use to be associated with improved 

outcomes of interest, the heterogeneity identified in our analyses appears related to variance in 

the precise magnitude of an overall consistent effect favoring metformin. 

Of note, because our syntheses relied on observational data, we were limited in our ability to 

assess publication bias as part of our review. Existing study registries (eg, ClinicalTtrials.gov) do 

not apply to observational studies, which precluded a statistical analysis of publication bias. 

FUTURE RESEARCH 

To date, many diabetes pharmacotherapy RCTs have excluded patients with CKD, advanced 

CHF, and other historical contraindications or precautions to metformin use. As such, the 

primary gap in the current evidence regarding metformin use in populations with traditional 

contraindications and precautions is the lack of randomized trials in this domain. Currently, 

various factors reduce the feasibility of conducting RCTs addressing the use of metformin in 

populations with traditional contraindications and precautions, including the fact that metformin 

is a generic medication widely considered to be the consensus first-line treatment for T2D. The 

length of time required for appropriate assessment of relevant outcomes may also be prohibitive. 

A large pragmatic trial akin to the Diuretic Comparison Project, an ongoing VA Cooperative 

Study comparing hydrochlorothiazide and chlorthalidone for cardiovascular risk reduction in 

hypertension,71 may be a feasible strategy for assessing the comparative effectiveness of 

metformin and other agents among patients with historical contraindications and precautions. 

Even without RCTs, new observational studies will remain important to ensure that rates of 

metformin-associated LA do not rise as metformin prescribing increases among populations with 

traditional contraindications (especially CKD). As the use of newer diabetes classes becomes 

more prevalent within VA, observational studies will remain a viable approach for comparing 

metformin with newer agents in these populations. 

The impact of contraindication or precaution severity on the apparently beneficial effects of 

metformin remains unclear based on available data. For example, while our primary CKD metaanalysis did include patients with eGFR down to 30 mL/min/1.73m2

, additional studies focusing 

specifically on cohorts with eGFR 30-45 mL/min/1.73m2

or even <30mL/min/1.73m2 would 

further inform prescribing of metformin in these groups, and refinement of clinical guidelines. 

Data regarding the impact of precaution severity in CHF, CLD, and older age are sparse, and 

further observational research could address these gaps. 

Building on the issue of severity, the possibility of tailoring prescribing recommendations based 

on the severity of historical contraindications or precautions would benefit from further research. 

For example, metformin dose reduction based on eGFR has long been recommended in Canadian 

prescribing guidelines,72 and US thought leaders have recently suggested a maximum metformin 

dose of 2550 mg for patients with eGFR >60, 2000 mg daily for eGFR 45-<60 mL/min/1.73m2

and 1000 mg/day for eGFR 30-<45 mL/min/1.73m2.

5 Given that the kidneys excrete metformin 

unchanged in the urine,73 the idea of such dose adjustment has a clear rationale, but at this time 

there are no experimental data and limited observational data to support such an approach. 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

39

Finally, data were particularly limited for certain conditions (eg, CLD) and outcomes of interest 

beyond mortality (eg, MACE, hypoglycemia); future observational research is warranted to 

explore these areas in greater detail. It will also be crucial to evaluate whether the mortality 

benefit associated with metformin use persists as prescribing in populations with historical

contraindications and precautions expands. 

CONCLUSIONS

Based on limited evidence, the rate of LA associated with metformin use among patients with 

historical contraindications or precautions does not appear higher than that of other diabetes 

medications. Metformin appears to be associated with reduced all-cause mortality in patients 

with CKD and patients with CHF, and appears to be associated with reduced CHF readmission in 

patients with CHF. Though data are otherwise limited, other risks of metformin use do not 

appear higher than those associated with other diabetes medications among patients with 

historical contraindications or precautions. Despite this review’s limitations, our findings support 

recent FDA labeling changes, may help inform clinical practice and revision of clinical 

guidelines, and point toward important areas for future research. 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

40

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827. 

74. Weir MA, Gomes T, Mamdani M, et al. Impaired renal function modifies the risk of 

severe hypoglycaemia among users of insulin but not glyburide: a population-based 

nested case-control study. Nephrol Dial Transplant. 2011;26(6):1888-1894. 
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APPENDIX A. FDA SAFETY ANNOUNCEMENTS FOR

METFORMIN

This appendix explains both the original and updated US Food and Drug Administration’s safety 

warnings in relation to the use of metformin. 

Original ALERT: U.S. Boxed Warning for Lactic Acidosis

Lactic acidosis is a rare but serious metabolic complication that can occur because of 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 or 

more), 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 of 5 mcg/mL or more are generally found. 

The reported incidence of lactic acidosis in patients receiving metformin is very low 

(approximately 0.03 cases per 1,000 patient-years, with approximately 0.015 fatal cases per 

1,000 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 function impairment, including 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 (CHF) requiring 

pharmacologic management, in particular those with unstable or acute CHF 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. Therefore, the risk of lactic 

acidosis may 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, accompany 

treatment of elderly patients with careful monitoring of renal function. Do not initiate metformin 

treatment in patients 80 years of age and older unless measurement of creatinine clearance (CrCl) 

demonstrates that renal function is not reduced because these patients are more susceptible to 

developing lactic acidosis. In addition, promptly withhold metformin in the presence of any 

condition associated with hypoxemia, dehydration, or sepsis. Because hepatic function 

impairment may significantly limit the ability to clear lactate, generally avoid using metformin in 

patients with clinical or laboratory evidence of hepatic disease. Caution patients against 

excessive alcohol intake, either acute or chronic, when taking metformin because alcohol 

potentiates the effects of metformin on lactate metabolism. In addition, temporarily discontinue 

metformin prior to any intravascular radiocontrast study and for any surgical procedure. 

The onset of lactic acidosis is often 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 health care provider must be aware of the 

possible importance of such symptoms. Instruct patients to notify their health care provider 

immediately if these symptoms occur. Withdraw metformin until the situation is clarified. Serum 

electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate levels, and even blood 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, GI 

symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later 

occurrence of GI symptoms could be caused by lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal (ULN) but less than 5 

mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and 

may be explained by other mechanisms, such as poorly controlled diabetes or obesity, vigorous 

physical activity, or technical problems in sample handling.

Suspect lactic acidosis 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, 

immediately discontinue the drug and promptly institute general supportive measures. Because 

metformin 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.

Updated Safety Announcement, April 8, 2016

FDA Drug SafetyCommunication:FDA revises warnings regarding use of the diabetes

medicinemetforminincertain patientswith reduced kidney function

The U.S. Food and Drug Administration (FDA) is requiring labeling changes regarding the

recommendations for metformin-containing medicinesfor diabetes toexpand metformin’s use in 

certain patients with reduced kidney function. The current labeling strongly recommends against

use of metformin in some patients whose kidneysdo not work normally. We were asked to review 

numerous medical studies regarding the safety of metformin use in patients with mild to moderate 

impairment in kidney function, and to change the measure of kidney function in the metformin drug

labeling that is used to determine whether a patient can receive metformin. We have concluded our 

review, and are requiring changes to the labeling of all metformin-containing medicinesto reflect this

new information.

Health care professionals should follow the latest recommendations when prescribingmetformincontaining medicines to patients with impaired kidney function. Patients should talk to their health 

care professionals if they have any questions or concerns about taking metformin.

Metformin-containing medicines are available by prescription only and are used alongwith diet and 

exercise to lower blood sugar levels in patients with type 2 diabetes (T2D). When untreated, T2D

can lead to serious problems, including blindness, nerve andkidney damage, and heart disease.

Metformin-containing medicines are available assingle-ingredient products and also in combination 

with other drugs used to treat diabetes (see FDA Approved metformin-containing Medicines). The 

current drug labeling strongly recommends against metformin use in some patients whose kidneys 

do not work normally because use of metformin in these patients can increase the risk of developing

a serious and potentially deadly condition called lactic acidosis, in which too much lacticacid 

builds up in the blood.
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We have concluded from the review of studies published in the medical literature that metformin 

can be used safely in patients with mild impairment in kidney function and in some patients with 

moderate impairment in kidney function. We are requiring changes to the metformin labeling to 

reflect this new information and provide specificrecommendations on the drug’s use in patients with 

mild to moderate kidney impairment.

We are also recommending that the measure of kidney function used to determinewhether a 

patient can receive metformin be changed from one based on a single laboratory parameter (blood 

creatinine concentration) to one that provides a betterestimate of kidney function in patients with 

kidney disease (i.e., glomerular filtration rate estimating equation [eGFR]).

Health care professionals and patients should report side effects involving metformin or other 

medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the 

bottom of this page.

FDA-approve d metformin-containing medicines*

Brand name Active ingredients

Actoplus Met metformin and pioglitazone

Actoplus Met XR metformin and pioglitazone, extended release

Avandamet metformin and rosiglitazone

Fortamet metformin extended release

Glucophage metformin

Glucophage XR metformin extended release

Glucovance metformin and glyburide

Glumetza metformin extended release

Invokamet metformin and canagliflozin

Janumet metformin and sitagliptin

Janumet XR metformin and sitagliptin, extended release

Jentadueto metformin and linagliptin

Kazano metformin and alogliptin

Kombiglyze XR metformin and saxagliptin, extended release

Prandimet metformin and repaglinide

Riomet metformin

Synjardy metformin and empagliflozin

Xigduo XR metformin and dapagliflozin, extended release

*These medicines are also available in multiple generic versions.

Facts about metformin

Metformin-containing medicines are available by prescription only and are used along with 

diet and exercise to treat type 2 diabetes.

Metformin helps control blood sugar in a number of ways. These include helping the body 

respond better to the insulin it makes naturally, decreasing the amount of sugar the liver 

makes, and decreasing the amount of sugar the intestines absorb from food.
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Metformin is available as a single-ingredient product and also in combination with other

medicines used to treat diabetes. See FDA Approved metformin- containing Medicines.

Common side effects of metformin include diarrhea, nausea, and upset stomach.

Additional information is available at: http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm

(Accessed July 1, 2016) 
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APPENDIX B. SEARCH STRATEGY 

Key Question 1—PubMed: November 20, 2015

Set Query Results

1 "Acidosis, Lactic"[Mesh] OR "Lactic Acid/blood"[Mesh] OR "lactic acidosis"[tiab] OR 

hyperlactatemia[tiab] OR hyperlactataemia[tiab] 13168

2 "Diabetes Mellitus"[Mesh] OR diabetes[tiab] OR diabetic[tiab] 513282

3 

"Renal Insufficiency, Chronic"[Mesh] OR "Heart Failure"[Mesh] OR "Hepatic 

Insufficiency"[Mesh] OR "Liver Cirrhosis"[Mesh] OR "Diabetic 

Nephropathies"[Mesh] OR "Aged"[Mesh] OR "Age Factors"[Mesh] OR 

"Geriatrics"[Mesh] OR CKD[tiab] OR CRD[tiab] OR "chronic kidney"[tiab] OR 

"chronic renal"[tiab] OR "heart failure"[tiab] OR CHF[tiab] OR "chronic liver 

disease"[tiab] OR "liver insufficiency"[tiab] OR "hepatic insufficiency"[tiab] OR "liver 

cirrhosis"[tiab] OR "diabetic nephropathies"[tiab] OR "diabetic nephropathy"[tiab]

OR aged[tiab] OR elderly[tiab] OR older[tiab] OR geriatric[tiab]

3427067

4 "Metformin"[Mesh] OR metformin[tiab] 13077

5 

(randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] 

OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR 

placebo[tiab] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] 

OR “clinical trial”[tiab] OR “clinical trials”[tiab] OR "evaluation studies"[Publication 

Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tiab] 

OR evaluation studies[tiab] OR "intervention studies"[MeSH Terms] OR 

"intervention study"[tiab] OR "intervention studies"[tiab] OR "comparative 

study"[Publication Type] OR "comparative study"[tiab] OR "case-control 

studies"[MeSH] OR "cohort studies"[MeSH] OR "Drug Information Services"[Mesh]

OR "case-control"[tiab] OR cohort[tiab] OR "longitudinal”[tiab] OR 

longitudinally[tiab] OR prospective[tiab] OR prospectively[tiab] OR 

"retrospective"[tiab] OR "follow up"[tiab] OR "Case Reports" [Publication Type] OR 

"case series"[tiab] OR pharmacovigilance[tiab]) NOT (Editorial[ptyp] OR 

Letter[ptyp] OR Comment[ptyp]) NOT (animals[mh] NOT humans[mh])

6464701

6 #1 AND (#2 OR #3) AND #4 AND #5 298

Key Question 2—PubMed: November 20, 2015

Set Query Results

1 "Diabetes Mellitus"[Mesh] OR diabetes[tiab] OR diabetic[tiab] 513282

2 

"Renal Insufficiency, Chronic"[Mesh] OR "Heart Failure"[Mesh] OR "Hepatic 

Insufficiency"[Mesh] OR "Liver Cirrhosis"[Mesh] OR "Diabetic 

Nephropathies"[Mesh] OR "Aged"[Mesh] OR "Age Factors"[Mesh] OR 

"Geriatrics"[Mesh] OR CKD[tiab] OR CRD[tiab] OR "chronic kidney"[tiab] OR 

"chronic renal"[tiab] OR "heart failure"[tiab] OR CHF[tiab] OR "chronic liver 

disease"[tiab] OR "liver insufficiency"[tiab] OR "hepatic insufficiency"[tiab] OR "liver 

cirrhosis"[tiab] OR "diabetic nephropathies"[tiab] OR "diabetic nephropathy"[tiab]

OR aged[tiab] OR elderly[tiab] OR older[tiab] OR geriatric[tiab] OR "Acidosis, 

Lactic"[Mesh] OR "Lactic Acid/blood"[Mesh] OR "lactic acidosis"[tiab] OR 

hyperlactatemia[tiab] OR hyperlactataemia[tiab] OR "Metformin/adverse 

effects"[Mesh]

3438398

3 "Metformin"[Mesh] OR metformin[tiab] 13077
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Set Query Results

4 

(randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] 

OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR 

placebo[tiab] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] 

OR “clinical trial”[tiab] OR “clinical trials”[tiab] OR "evaluation studies"[Publication 

Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tiab] 

OR evaluation studies[tiab] OR "intervention studies"[MeSH Terms] OR 

"intervention study"[tiab] OR "intervention studies"[tiab] OR "comparative 

study"[Publication Type] OR "comparative study"[tiab] OR "cohort studies"[MeSH] 

OR cohort[tiab] OR "longitudinal”[tiab] OR longitudinally[tiab] OR prospective[tiab] 

OR prospectively[tiab] OR "retrospective"[tiab] OR "follow up"[tiab]) NOT 

(Editorial[ptyp] OR Letter[ptyp] OR Comment[ptyp] OR "Case Reports" [Publication 

Type]) NOT (animals[mh] NOT humans[mh])

4823517

5 #1 AND #2 AND #3 AND #4 2218

Key Question 1—Embase: November 20, 2015

Set Query Results

1 'lactic acidosis'/exp OR 'lactic acid'/exp OR "lactic acidosis":ab,ti OR 

hyperlactatemia:ab,ti OR hyperlactataemia:ab,ti 67408

2 'diabetes mellitus'/exp OR diabetes:ab,ti OR diabetic:ab,ti 825055

3 

'chronic kidney failure'/exp OR 'heart failure'/exp OR 'liver failure'/exp OR 'liver 

cirrhosis'/exp OR 'diabetic nephropathy'/exp OR 'aged'/exp OR 'age'/exp OR 

'geriatrics'/exp OR CKD:ab,ti OR CRD:ab,ti OR "chronic kidney":ab,ti OR "chronic 

renal":ab,ti OR "heart failure":ab,ti OR CHF:ab,ti OR "chronic liver disease":ab,ti 

OR "liver insufficiency":ab,ti OR "hepatic insufficiency":ab,ti OR "liver 

cirrhosis":ab,ti OR "diabetic nephropathies":ab,ti OR "diabetic nephropathy":ab,ti

OR aged:ab,ti OR elderly:ab,ti OR older:ab,ti OR geriatric:ab,ti

4045218

4 'metformin'/exp OR metformin:ab,ti 41795

5 

('randomized controlled trial'/exp OR 'crossover procedure'/exp OR 'double blind 

procedure'/exp OR 'single blind procedure'/exp OR random*:ab,ti OR 

factorial*:ab,ti OR crossover*:ab,ti OR (cross NEAR/1 over*):ab,ti OR 

placebo*:ab,ti OR (doubl* NEAR/1 blind*):ab,ti OR (singl* NEAR/1 blind*):ab,ti OR 

assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR 'clinical study'/exp OR 

'clinical trial':ti,ab OR ‘clinical trials’:ti,ab OR 'controlled study'/exp OR 

'evaluation'/exp OR ‘evaluation study’:ab,ti OR ‘evaluation studies’:ab,ti OR 

‘intervention study’:ab,ti OR ‘intervention studies’:ab,ti OR ‘case control’:ab,ti OR 

'cohort analysis'/exp OR cohort:ab,ti OR longitudinal*:ab,ti OR prospective:ab,ti OR 

prospectively:ab,ti OR retrospective:ab,ti OR 'follow up'/exp OR ‘follow up’:ab,ti OR 

'comparative effectiveness'/exp OR 'comparative study'/exp OR ‘comparative 

study’:ab,ti OR ‘comparative studies’:ab,ti OR 'drug surveillance program'/exp OR 

pharmacovigilance:ab,ti OR 'case report'/exp OR 'case study'/exp OR 'case 

series":ab,ti) NOT ('editorial'/exp OR 'letter'/exp OR 'note'/exp)

11802586

6 #1 AND (#2 OR #3) AND #4 AND #5 1205

7 #6 AND [embase]/lim NOT [medline]/lim 387
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Key Question 2—Embase: November 20, 2015

Set Query Results

1 'diabetes mellitus'/exp OR diabetes:ab,ti OR diabetic:ab,ti 825055

2 

'chronic kidney failure'/exp OR 'heart failure'/exp OR 'liver failure'/exp OR 'liver 

cirrhosis'/exp OR 'diabetic nephropathy'/exp OR 'aged'/exp OR 'age'/exp OR 

'geriatrics'/exp OR CKD:ab,ti OR CRD:ab,ti OR "chronic kidney":ab,ti OR "chronic 

renal":ab,ti OR "heart failure":ab,ti OR CHF:ab,ti OR "chronic liver disease":ab,ti 

OR "liver insufficiency":ab,ti OR "hepatic insufficiency":ab,ti OR "liver 

cirrhosis":ab,ti OR "diabetic nephropathies":ab,ti OR "diabetic nephropathy":ab,ti

OR aged:ab,ti OR elderly:ab,ti OR older:ab,ti OR geriatric:ab,ti OR 'lactic 

acidosis'/exp OR 'lactic acid'/exp OR "lactic acidosis":ab,ti OR 

hyperlactatemia:ab,ti OR hyperlactataemia:ab,ti OR 'metformin'/exp/dd_ae

4104859

3 'metformin'/exp OR metformin:ab,ti 41795

4 

('randomized controlled trial'/exp OR 'crossover procedure'/exp OR 'double blind 

procedure'/exp OR 'single blind procedure'/exp OR random*:ab,ti OR 

factorial*:ab,ti OR crossover*:ab,ti OR (cross NEAR/1 over*):ab,ti OR 

placebo*:ab,ti OR (doubl* NEAR/1 blind*):ab,ti OR (singl* NEAR/1 blind*):ab,ti OR 

assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR 'clinical study'/exp OR 

'clinical trial':ti,ab OR ‘clinical trials’:ti,ab OR 'controlled study'/exp OR 

'evaluation'/exp OR ‘evaluation study’:ab,ti OR ‘evaluation studies’:ab,ti OR 

‘intervention study’:ab,ti OR ‘intervention studies’:ab,ti OR 'cohort analysis'/exp OR 

cohort:ab,ti OR longitudinal*:ab,ti OR prospective:ab,ti OR prospectively:ab,ti OR 

retrospective:ab,ti OR 'follow up'/exp OR ‘follow up’:ab,ti OR 'comparative 

effectiveness'/exp OR 'comparative study'/exp OR ‘comparative study’:ab,ti OR 

‘comparative studies’:ab,ti) NOT ('case report'/exp OR 'case study'/exp OR 'case 

series":ab,ti OR 'editorial'/exp OR 'letter'/exp OR 'note'/exp)

9867450

5 #1 AND #2 AND #3 AND #4 8122

6 #5 AND [embase]/lim NOT [medline]/lim 2610

Key Question 2—Cochrane Central Register of Controlled Trials: November 20, 

2015

Set Terms Results

1 [mh "Diabetes Mellitus"] 17098

2 diabetes:ab,ti OR diabetic:ab,ti 36056

3 #1 OR #2 37538

4 

[mh "chronic Renal Insufficiency"] OR [mh "Heart Failure"] OR [mh "Hepatic 

Insufficiency"] OR [mh "Liver Cirrhosis"] OR [mh "Diabetic Nephropathies"] OR [mh 

Aged] OR [mh "Age Factors"] OR [mh Geriatrics] OR [mh "lactic Acidosis"] OR [mh 

"Lactic Acid"] OR [mh Metformin/AE]

24846

5 

"lactic acidosis":ab,ti OR hyperlactatemia:ab,ti OR hyperlactataemia:ab,ti OR

CKD:ab,ti OR CRD:ab,ti OR "chronic kidney":ab,ti OR "chronic renal":ab,ti OR 

"heart failure":ab,ti OR CHF:ab,ti OR "chronic liver disease":ab,ti OR "liver 

insufficiency":ab,ti OR "hepatic insufficiency":ab,ti OR "liver cirrhosis":ab,ti OR 

"diabetic nephropathies":ab,ti OR "diabetic nephropathy":ab,ti OR aged:ab,ti OR 

elderly:ab,ti OR older:ab,ti OR geriatric:ab,ti

85344

6 #4 OR #5 98264

7 [mh Metformin] 1651

8 Metformin:ab,ti 3292

9 #7 OR #8 3417

10 #9 AND #6 AND #3 471

11 Limit: Cochrane Central Register of Controlled Trials 454
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APPENDIX C. QUALITY ASSESSMENT FOR RANDOMIZED 

CONTROLLED TRIALS

QUALITY CRITERIA

General instructions: Rate each risk of bias item listed below as “Low,” “High,” or “Unclear.” 

Rating of individual items for study #________ : 

1. Selection bias

a. Domain: Random sequence generation

(Support for judgement: Describe the method used to generate the allocation sequence in sufficient 

detail to allow an assessment of whether it should produce comparable groups.)

Was the allocation sequence adequately generated?

Low risk High risk Unclear risk 

b. Domain: Allocation concealment?

(Support for judgement: Describe the method used to conceal the allocation sequence in sufficient 

detail to determine whether intervention allocations could have been foreseen in advance of, or during, 

enrolment)

Was allocation adequately concealed?

Low risk High risk Unclear risk 

2. Performance bias

Domain: Blinding of participants and "treating" personnel - i.e. the person(s) delivering the 

intervention.

(Support for judgement: Describe all measures used, if any, to blind study participants and personnel 

from knowledge of which intervention a participant received. Provide any information relating to whether 

the intended blinding was effective.)

Was knowledge of the allocated intervention adequately prevented during the study?

Low risk High risk Unclear risk Outcome NR 

3a. Detection bias (outcome 1 = ) 

Domain: Blinding of outcome assessment

(Support for judgement: Describe all measures used, if any, to blind outcome assessors from 

knowledge of which intervention a participant received. Provide any information relating to whether the 
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intended blinding was effective.)

Was knowledge of the allocated intervention adequately prevented from outcome assessors?

Low risk High risk Unclear risk Outcome NR 

3b. Detection bias (outcome 2 = ) 

Domain: Blinding of outcome assessment

(Support for judgement: Describe all measures used, if any, to blind outcome assessors from 

knowledge of which intervention a participant received. Provide any information relating to whether the 

intended blinding was effective.)

Was knowledge of the allocated intervention adequately prevented from outcome assessors?

Low risk High risk Unclear risk Outcome NR 

3c. Detection bias (outcome 3 = ) 

Domain: Blinding of outcome assessment

(Support for judgement: Describe all measures used, if any, to blind outcome assessors from 

knowledge of which intervention a participant received. Provide any information relating to whether the 

intended blinding was effective.)

Was knowledge of the allocated intervention adequately prevented from outcome assessors?

Low risk High risk Unclear risk Outcome NR 

3d. Detection bias (outcome 4 = ) 

Domain: Blinding of outcome assessment

(Support for judgement: Describe all measures used, if any, to blind outcome assessors from 

knowledge of which intervention a participant received. Provide any information relating to whether the 

intended blinding was effective.)

Was knowledge of the allocated intervention adequately prevented from outcome assessors?

Low risk High risk Unclear risk Outcome NR 

4. Attrition bias

Domain: Incomplete outcome data 

(Support for judgement: Describe the completeness of outcome data for each main outcome, including 
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attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the 

numbers in each intervention group (compared with total randomized participants), reasons for 

attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors.)

Were incomplete outcome data adequately addressed?

Low risk High risk Unclear risk 

5. Reporting bias

Domain: Selective outcomes reporting 

(Support for judgement: State how the possibility of selective outcome reporting was examined by the 

review authors, and what was found.)

Are reports of the study free of suggestion of selective outcome reporting? (i.e., the author states 

they will measure an outcome but do not report it)

Low risk High risk Unclear risk 

6. Other

Domain: Other sources of bias

(Support for judgement: State any important concerns about bias not addressed in the other domains 

in the tool. If particular questions/entries were pre-specified in the review’s protocol, responses should 

be provided for each question/entry.)

Are reports of the study free from other bias due to problems not covered above?

Low risk High risk Unclear risk Describe:

Overall risk of bias rating

Low risk 

Unclear risk 

High risk 

* Items contained in the Cochrane Risk of Bias Tool
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QUALITY ASSESSMENT RESPONSE TABLE—RCTS

For full study citations, please refer to the report’s main reference list.

Studya 1a 1b 2 3a 3b 3c 3d 4 5 6 Overall Risk of 

Bias Rating

Blonde, 200251 Unclear Unclear Low Low Low NA NA Unclear Low Unclear Unclear

Cryer, 200552 Unclear Unclear High NAb Low Unclear NA Low Low Low Low

Garber, 200253 Unclear Unclear Low Low Low NA NA Unclear Low Unclear Unclear

Gregorio, 

199954 Low Unclear Unclear Unclear NR Low NR Low Low Low High

Hanefeld, 

200455 Low Unclear Unclear Low NA Unclear Low Low NA Low Low

Marre, 200256 Unclear Unclear Low Low Low NA NA Unclear Low Unclear Unclear

Schweizer, 

200957 Unclear Unclear Low Low Low Low NA Low Low Low Low

a The companion paper does not appear in this table.

b For mortality, blinding does not apply.
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APPENDIX D. QUALITY ASSESSMENT FOR 

OBSERVATIONAL STUDIES 

QUALITY CRITERIA

This tool is intended to evaluate the quality of observational studies examining the outcomes of 

metformin use in patients with contraindications/precautions. Use this risk of bias tool for the 

following study designs: nonrandomized controlled trial, cohort studies, and case-control studies. 

Each item that is marked “C” applies to nonrandomized trials and cohort studies, “CC” to casecontrol studies, and “CS” to case-series.

Instructions for use:

1. Items are organized by risk of bias domains (selection, performance, attrition, detection and 

reporting bias). Rate each question using the response categories listed. Focus on study design 

and conduct, not quality of reporting. 

2. Two questions: basic study design, sample size/power are not used in the overall ratings but 

are collected for descriptive purposes.

3. After answering each item, rate the study overall as “low risk of bias,” “moderate risk of bias,” 

or “high risk of bias” based on the following definitions. This overall rating is specific to the 

basic study design used. For example, if the basic study design was a cohort study, then the risk 

of bias rating would be interpreted as “For a cohort study, the risk of bias is ______.” 

“Low Risk of Bias” study has the least bias, and results are considered valid. A 

good study has a clear description of the population, setting, interventions, and 

comparison groups; uses recruitment and eligibility criteria that minimizes 

selection bias; has a low attrition rate; and uses appropriate means to prevent bias, 

measure outcomes, and analyze and report results. These studies will meet the 

majority of items in each domain.

“Moderate Risk of bias” study is susceptible to some bias but probably not 

enough to invalidate the results. The study may be missing information, making it 

difficult to assess limitations and potential problems. As the fair-quality category 

is broad, studies with this rating vary in their strengths and weaknesses. The 

results of some fair-quality studies are possibly valid, while others are probably 

valid. These studies will meet the majority of items in most but not all domains.

“High Risk of Bias” rating indicates significant bias that may invalidate the 

results. These studies have serious errors in design, analysis, or reporting; have 

large amounts of missing information; or have discrepancies in reporting. The 

results of a poor-quality study are at least as likely to reflect flaws in the study 

design as to indicate true differences between the compared interventions.
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1. Basic Design 

Is the study design prospective, retrospective, or mixed? [Abstractor: Prospective design 

requires that the investigator plans a study before any data are collected. Mixed design 

includes case-control, nested case-control, or cohort studies in which one group is 

studied prospectively and the other retrospectively.]

Prospective Mixed Retrospective Cannot determine

2. Selection Bias

2.1 Inclusion/exclusion criteria [C, CC, CS]

a. Are the inclusion/exclusion criteria clearly stated (does not require the reader to 

infer)? [Key eligibility criteria are: age, diabetes type/level of control, use of 

metformin and/or other hypoglycemic medication, presence of metformin 

contraindication/precaution, certain comorbidities. Abstractor: use “Partial” if 

only some criteria are stated or if some criteria are not clearly stated.]

Yes Partial No

b. Did the study apply valid and reliable measures to determine inclusion/exclusion 

criteria that were applied criteria uniformly to all comparison groups i.e., the 

group on metformin and the group not on metformin? [C, CC] Pay particular 

attention to determination of DM2 and precaution. Measures accepted:

T2D: ICD codes or medical record diagnosis; ≥ 2 HbA1c measures with values ≥

6.5, FBS values > 126 mg/dl

Use of metformin: prescription, pharmacy database, medical record. If reported, 

please note whether it is incident use of metformin or prevalence of metformin 

use or NR in the text box.

Precautions: Age – take whatever is given; Liver disease – biopsy, imaging 

(fibrscan or CT), ICD codes, medical record diagnosis; CHF – echo or other 

cardiac imaging, ICD codes, medical record IF structured criteria (eg, BNP, list of 

symptoms, PE findings); CKD – eGFR <60, 90 days apart, ICD codes or medical 

record diagnosis

Yes Partial No Not applicable (no comparator)

2.2. Recruitment (prospective studies only): [Prospective Cohort]

Did the strategy for recruiting/entering participants into the study differ across study 

groups? 

Yes No Cannot determine NA (retrospective)

2.3 Baseline characteristics similar or appropriate adjusted analysis [C]

Are key characteristics of study participants [age, race, gender, diabetes severity, 

metformin contraindications/precautions, etc.] similar between intervention and 

comparator groups? If not similar, did the analyses appropriately adjust for important 

differences [Design: stratification, matching; Analysis: multiple regression, propensity 

score adjustment, etc.]? Pay particular attention to whether the metformin precautions are 
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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similar between groups, i.e., rates of CHF, levels of kidney function, and prevalence of 

liver disease.

Yes Partial No NA (no comparison group)

2.4 Comparison Group (KQ1b/2 only) [C, CC] 

 Is the selection of the comparison group appropriate? [Comparison group must include 

DM2 patients with a precaution of interest – then, less importantly, other DM treatment, 

eg, exposed to one or more non-metformin hypoglycemic medications.] 

Yes No Cannot determine NA (KQ1a)

3. Performance Bias [C, CC, CS]

 Were metformin and comparison group patients treated similarly? Or was there a 

difference that might affect outcomes? If so, in selecting the population or analyzing the 

data, did researchers rule out any impact from a concurrent intervention or an unintended 

exposure that might bias results? For example:

a. for MALA, are there other likely causes of LA?

b. for hypoglycemia, consider use of other hypoglycemics, especially insulin, 

when metformin use is not the only difference between groups, 

c. for A1c, are there differences in treatment other than metformin, especially 

insulin or very intense lifestyle intervention program? 

d. for mortality or CV mortality, was overall management of other disease states 

comparable – HTN treatment, use of statins, etc., 

e. For MACE (major adverse cardiovascular events, eg, MI, hospitalization, 

CHF) consider that same concern about equitable treatment for other disease 

states between groups. 

Yes Partial No Unclear NA

4. Attrition Bias

4.1 Equality of length of follow-up for participants [C, CC]

In cohort studies, is the length of follow-up similar between the groups, or appropriately 

accounted for using statistical techniques? For case-control studies, is the time period 

between the intervention/exposure and outcome the same for cases and 

controls?[Abstractor: Where follow-up was the same for all study patients the answer is 

yes. If different lengths of follow-up were adjusted by statistical techniques, for example, 

Box given on form for comments on Selection bias: 

Box given on form for comments on Performance bias: 
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survival analysis, the answer is yes. Studies where meaningful differences in follow-up 

are ignored should be answered no. A meaningful difference is more than 3 months.] 

Yes No Unclear NA

4.2 Completeness of follow-up [C, CC]

Was there a low rate of differential or overall attrition? [Attrition is measured in relation 

to the time between baseline (allocation in some instances) and outcome measurement. 

Standard for overall attrition is <20 percent for <1 year f/u and <30 percent for longer 

term ≥ 1 year). Standard for differential attrition is ≥ 10% absolute difference. Pay 

particular attention it this is a KQ1 study on LA or MALA as differential drop-out is 

more problematic in these studies.]

Yes No Unclear NA

4.3 Attrition affecting Participant Composition [C]

Was attrition small enough that it did not result in a difference in group characteristics 

between baseline and follow-up? 

Yes No Unclear NA

5. Detection Bias

5.1 Blind outcomes assessment [C, CC, CS; doesn’t apply to MALA or mortality]

Were the outcome assessors blinded to the intervention or exposure status of participants? 

[If outcomes based on clinical codes, then “No” unless additional review because they are 

determined clinically]

Yes No NA (not an intervention study)

5.2 Source of information: Outcomes

Are primary outcomes (eg, LA, MACE, mortality) assessed using valid and reliable 

measures and implemented consistently across all study participants? 

[LA is defined typically as blood lactate concentration >45mg/dl or 5.0mEq/L, 

decreased blood pH, and electrolyte disturbances with an increased anion gap. 

MALA is defined as meeting the definition for LA plus either (a) elevated metformin level 

or (b) investigator judgment that LA is metformin-induced.] 

Yes No Cannot determine (measurement not reported)

Box given on form for comments on Attrition bias: 
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5.3 . Are confounding variables assessed using valid and reliable measures, implemented 

consistently across all study participants? [Major potential confounders include: age, 

race, gender, diabetes severity (i.e. glycemic control and complications), comorbidities, 

metformin contraindications/precautions, etc.] 

Yes Partial No Cannot determine

6. Reporting Bias

Are findings for all primary outcomes reported? [Abstractor needs to identify all prespecified, primary outcomes that should be reported in the study.]

Yes Partially (some outcomes NR) No (Primary outcomes not prespecified)

7. Other Risk of Bias Issues [C, CC, CS]

No (no other concerns present) Yes (other concerns present) 

Box given on form for comments on Detection bias: 

Box given on form for comments on Detection bias:
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QUALITY ASSESSMENT RESPONSES—OBSERVATIONAL STUDIES

For full study citations, please refer to the report’s main reference list.

Study 1 2.1a 2.1b 2.2 2.3 2.4 3 4.1 4.2 4.3 5.1 5.2 5.3 6 7 Overall Risk 

of Bias Rating

Aguilar, 201141 Ret Yes Yes NA Yes Yes Par Yes Yes Yes Yes Yes Yes Yes Yes Low

Ampuero, 201249 Ret Par Par NA Yes Yes Yes Yes Yes Yes NA Yes Par Yes No Mod

Andersson, 201025 Ret Yes Par NA Yes Yes Yes Unc Unc Unc No Yes Yes Yes No Mod

Bannister, 201458 Ret Yes Par NA Par Yes Unc Yes Yes Yes NA Yes Unc Yes No Mod

Becquemont, 201539 Pro Yes NA No NA NA Yes NA Unc Unc NA Unc Unc Yes Yes High

Bodmer, 200859 Mix Yes Yes NA Yes Yes Unc Yes Unc NA NA Yes Yes Yes No Low

Ekstrom, 201240 Ret Yes Yes NA Yes Yes Yes Yes Unc Unc No Yes Yes Yes None Mod

Eppenga, 201434 Ret Par No NA Yes No Yes Yes Unc Yes No Yes Yes Yes No Mod

Eurich, 200526 Ret Par Par NA Yes Yes Yes Yes Unc Unc No Yes Yes Yes No Mod

Evans, 201045 Ret Yes Yes NA Yes Yes Yes Unc Unc Unc NA Yes Yes Yes No Mod

Huizinga, 201060 Ret Yes Par NA Par Yes Yes Yes No Unc Yes Yes Yes Yes Yes Mod

Inzucchi, 200546 Ret Yes Yes NA Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Low

Ito, 201136 Ret Yes Yes NA No Yes Unc Unc Unc Unc No Unc No Yes No High

Leung, 201061 Pro Par Par Unc No Unc Unc Unc Unc Unc No Yes No Yes No High

Masoudi, 200542 Ret Yes Yes NA Par Yes Yes Yes Yes Yes No Yes Par Par Yes Mod

Morgan, 201443 Ret Yes Yes NA Yes Yes Yes Yes Unc Yes NA Yes Yes Yes No Low

Nkontchou, 201150 Pro Yes Yes No No Unc Yes Yes Yes Yes NA Unc Unc Yes Yes High

Richy, 201433 Ret Yes Yes NA No NA No Yes Unc Unc No Yes Yes Yes Yes High

Romero, 201335 Pro Yes Yes No Yes Yes Yes Yes Unc Unc Yes Yes Yes Yes Yes Low

Roumie, 201262 Ret Yes Yes NA Yes Yes Yes Unc Yes Yes NA Yes Yes Yes No Low

Roussel, 201044 Pro Yes Par No Par Yes Par Yes No Unc NA Yes Yes Yes No Mod

Shah, 201047 Ret Yes Yes NA Par Yes Par Unc Unc Unc NA Yes Yes Yes No Mod

Sterner, 201237 Ret Par Par NA NA NA Yes Unc Unc Unc No Yes Unc Yes High
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Study 1 2.1a 2.1b 2.2 2.3 2.4 3 4.1 4.2 4.3 5.1 5.2 5.3 6 7 Overall Risk 

of Bias Rating

Tinetti, 201548 Ret Yes Yes NA Yes Yes Yes Yes Unc Unc NA Yes Unc Yes No Mod

Tzoulaki, 200964 Ret Yes Yes NA Yes Yes Yes Yes Yes Yes NA Yes Yes Yes No Low

Wang, 201463 Ret Yes Yes NA Yes Yes Yes Unc Unc Unc NA Yes Yes Yes Yes Mod

Weir, 201174 Ret Yes Par NA Yes Yes Yes Unc Unc Unc No Yes Yes Yes No Mod

Weir, 201427 Ret Par Par NA Yes Yes Yes Unc Unc Unc Yes Yes Yes Yes No Mod

Zhang, 200838 Ret Yes Yes NA Yes Yes Yes Unc Yes Yes NA Yes Yes Yes No Low

Abbreviations: Mix = Mixed; Mod = Moderate; Par = Partial; Pro = Prospective; Ret = Retrospective; Unc = Unclear
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APPENDIX E. PEER REVIEW COMMENTS/AUTHOR RESPONSES

Reviewer Comment Response

Question 1. Are the objectives, scope, and methods for this review clearly described?

1 Yes Acknowledged

3 Yes Acknowledged

4 Yes Acknowledged

Question 2. Are there any published or unpublished studies that we may have overlooked?

1 No Acknowledged

3 No Acknowledged

4 Yes - A recent meta-analysis examined comparative effectiveness of glucoselowering agents with respect to CV mortality, as well as several other outcomes: 

all-cause mortality, serious adverse events, myocardial infarction, stroke, HbA1c 

level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and 

weight (Palmer et al. Comparison of Clinical Outcomes and Adverse Events 

Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes JAMA 

July 19, 2016). In that meta-analysis, there were no significant differences in 

associations between any drug class as monotherapy, dual therapy, or triple 

therapy with odds of cardiovascular or all-cause mortality (including metformin). 

The meta-analysis came out after the authors submitted their review, but I 

recommend that they include this in their discussion and specifically address why 

their findings were different from the findings of the meta-analysis with respect to 

CV and all-cause mortality outcomes.

Thank you for identifying this recent review by 

Palmer et al. We added a discussion of the 

review’s findings and how they relate to our 

results. 

Question 3. Is there any indication of bias in our synthesis of the evidence?

1 No Acknowledged

3 No Acknowledged

4 No Acknowledged
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Reviewer Comment Response

Question 4: Please write additional suggestions or comments below. If applicable, please indicate the page and line numbers from the 

draft report.

1 Very useful ESP document, and as usual, very well done. Despite the fact that 

FDA released new guidance after this was commissioned, the review remains 

very relevant- and in fact may be even more important as this document states, it 

is likely that metformin will be used more often in "higher risk" populations.

Just a couple of minor thoughts:

1) "Black Box" on page 6, line 56-57: The correct term would be "boxed warning". 

FDA does not recognize the Black Box terminology. Not a big deal if left in.

2) Limitations: You might add that most of the studies compared metformin to 

sulfonylureas and to a lesser extent, TZDs. Both of these drug classes have their 

issues- and so it might be reasonable to acknowledge that the comparisons do 

not include the newer anti-diabetic agents.

3) Likewise- research should make these same comparisons with newer agents.

THANKS AGAIN to ESP for doing this review.

Thank you.

1) Thank you for this correction. The wording 

has been changed as recommended.

2) A statement about the majority of 

comparisons being to sulfonylureas and

thiazolidinediones has been added to limitations.

3) A statement about the need for these 

comparisons has been added to future research.

3 The review was comprehensive, and appropriately noted that limitations of the 

observational data literature.

Thank you.

4 The authors reviewed the use of metformin among patients with relative 

contraindications or precautions to its use, compared the risk of lactic acidosis 

among users of metformin versus users of other glucose-lowering agents, and 

compared other outcomes association with the use of metformin versus other 

glucose-lowering agents. The review focuses on an important clinical question 

and is well executed and well written.

Specific concerns:

Thank you.
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Reviewer Comment Response

4 continued KQ2: Limited data exist with respect to comparative benefits and harms of 

glucose-lowering agents. Authors have selected several outcomes for evaluation: 

glycemic control, lipid control, MACE, CV mortality, all-cause mortality, 

hypoglycemia, and weight gain. I recommend discussing rationale for the 

selection of these outcomes. What about other outcomes of importance to 

patients, such as microvascular complication rates, health-related quality of life? I 

understand there are limited data with respect to these outcomes, but this should 

not preclude them being included as a key question (which perhaps can’t be 

answered at this time).

Inclusion and exclusion criteria: I agree with the authors’ decision to include 

studies with the outcome of lactic acidosis (high lactate, low pH, and high anion 

gap). This definition of lactic acidosis should be stated in the text (currently as 

footnote to Table 2). This is an important point since there are some studies, 

which examined lactate levels alone; lactate levels are poor surrogates for lactic 

acidosis.

Page 15, lines 40-52: Recommend including information on what percentage of 

studies included in Salpeter’s review had stated contraindications to metformin 

use.

Outcomes selected for evaluation were 

prioritized with input from our stakeholders and 

Technical Expert Panel. We have added this 

detail to the Methods section. 

Acknowledged and thank you. We have added 

the definition of lactic acidosis to the 

introduction.

Because of limitations in the reporting of trial 

eligibility criteria, the Salpeter review concluded 

“There was insufficient information to estimate 

the number of participants studied with 

hypoxemic co-conditions such as renal 

insufficiency, cardiovascular diseases, liver 

diseases, or pulmonary disease.” A statement to 

this effect has been added to the results section 

of KQ 1.
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Reviewer Comment Response

4 continued CV mortality and all-cause mortality: A recent meta-analysis examined 

comparative effectiveness of glucose-lowering agents with respect to CV 

mortality, as well as several other outcomes: all-cause mortality, serious adverse 

events, myocardial infarction, stroke, HbA1c level, treatment failure (rescue 

treatment or lack of efficacy), hypoglycemia, and weight (Palmer et al. 

Comparison of Clinical Outcomes and Adverse Events Associated With GlucoseLowering Drugs in Patients With Type 2 Diabetes JAMA July 19, 2016). In that 

meta-analysis, there were no significant differences in associations between any 

drug class as monotherapy, dual therapy, or triple therapy with odds of 

cardiovascular or all-cause mortality (including metformin). The meta-analysis 

came out after the authors submitted their review, but I recommend that they 

include this in their discussion and specifically address why their findings were 

different from the findings of the meta-analysis with respect to CV and all-cause 

mortality outcomes.

Page 32, lines 45-50: Lack of evidence with respect to harm does not necessarily 

mean that the harm does not exist. Overall, the studies included in the systematic 

review had moderate risk of bias, with no existing randomized clinical trials 

designed to assess the safety of the use of metformin in patients with CKD with 

respect to lactic acidosis. Therefore, I recommend that some of the conclusions 

are restated to reflect ongoing uncertainty.

Tables 9 and 10 are very clear and nicely represent the SOE summary. Strengths 

and limitations section is well balanced. Discussion of the recent FDA 

recommendations for new labeling changes for metformin is important and well 

executed.

Thank you for identifying this recent review by 

Palmer et al. We have added a discussion of the 

review’s findings and how they relate to our 

results. 

We incorporated findings from the Palmer 

review (as noted previously) and describe the 

uncertainty this introduces and the need for 

large pragmatic comparative effectiveness trials. 

We also describe how the change in FDA 

guidance is likely to make future observational 

studies more useful.

Thank you.
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APPENDIX F. STUDY CHARACTERISTICS TABLES

Table 1. KQ 1 Study Characteristics by Condition

Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparatora

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Chronic kidney 

disease (CKD)

Becquemont, 201539

Prospective cohort

France

NR 

KQ 1a only

T2D: diagnosis, Rx

CKD: eGFR

category (based on 

whether metformin 

was adapted to 

eGFR)

Metformin use assessed 

prospectively

Median dose 2000mg 

daily (IQR 1700-2550)

Comparator: NA

LA: not specified

Event rate

Mean 3 years

No timeadjusted 

analysis

Age, eGFR High

Ekstrom 201240

Retrospective cohort, 

population-based

Sweden

Government 

 

KQ 1a and 1b

T2D: diagnosis, Rx

CKD: eGFR 

category (45-60, 30-

45)

12 months use of 

metformin 

Median dose 1100-

1900mg

Comparator: 12 months 

use of other oral 

antidiabetic agent (dose 

NR)

LA or serious 

infection: defined by 

diagnostic code

Event rate, hazard 

ratio

Mean 3.9 

years

No timeadjusted 

analysis

Age, sex, 

HbA1c, 

smoking, BMI, 

eGFR, 

comorbidities, 

medications

Mod

Eppenga, 201434

Retrospective cohort, 

population-based

Great Britain

Government, Industry 

KQ 1a and 1b

T2D: Rx

CKD: eGFR 

category >60, 45-

59, 30-44, <30

Current metformin use 

Stratified by yearly or 

daily dose

Comparator: never use 

of metformin but current 

use of other NIAD

LA: defined by Read 

code or lactate >5 

mmol/L

Event rate, hazard 

ratio 

Mean 4.3 

years

Time-adjusted 

analysis using 

intervals

Age, sex, BMI, 

CHF, 

medications

Mod
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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparatora

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Richy, 201433

Retrospective cohort, 

population-based

Great Britain

Industry

KQ 1a only

T2D: diagnosis, Rx

CKD: eGFR 

category >90, >60-

90, >30-60, <30

Any metformin Rx

Dose NR

Comparator: NA

LA: defined by ICD-9, 

fatal LA if death 

within 14 days 

Incidence rate

Mean 4.35 

years

Time-adjusted 

analysis using 

person-years

None High

Congestive heart 

failure (CHF)

Andersson, 201025

Retrospective cohort, 

population-based

Denmark

Government

KQ 1a and 1b

T2D: Rx

CHF: First CHF 

hospitalization 

based on diagnostic 

codes

Metformin use based on 

Rx records

Dose NR

Comparator: multiple 

comparator arms

LA: defined by ICD-9

Event rate

Median 844 

days

Secondary 

time-adjusted 

analysis 

based on 

individual drug 

coverage

Year, age, sex, 

Charlson, 

diabetes 

complications, 

medications 

(but NA here)

Mod

Romero, 201335

Prospective cohort, 

community-based

Spain

Government

KQ 1a and 1b

T2D: diagnosis, Rx, 

laboratory values

CHF: Framingham 

criteria

Metformin use based on 

Rx records

Dose NR

Comparator: no 

metformin use (dose 

NR)

LA: NR

Event rate

Median 56.9 

months

Time-adjusted 

analysis using 

person-years

Multivariate

analysis (but 

NA here) 

Low
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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparatora

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Liver disease

Zhang, 201438

Retrospective cohort, 

population-based

USA

Government

KQ 1a and 1b

T2D: diagnosis by 

clinician, Rx, selfreport, or laboratory 

values

Liver disease:

biopsy-proven 

cirrhosis with 

additional clinical 

evaluation

Continuation or 

discontinuation of 

metformin after cirrhosis 

(defined as cessation of 

metformin within 3 

months after diagnosis)

Dose NR

Comparator: 

discontinued metformin 

use

LA: categorical

Mortality: 10-year 

survival; categorical

5-10 years Age, sex,

albumin, MELD 

score, AFP 

level, etiology 

of cirrhosis

Low

Older adults

Ito, 201136

Pharmacovigilance

Japan

NR

KQ 1a only

Rx, laboratory

Exclusion: receiving 

unknown 

combination drugs, 

poor drug 

compliance, unclear 

initiation date of 

metformin, surgery

Metformin: 250mg, 

500mg, 750mg, 1000mg 

(majority 750mg) 

Comparator: NA

LA: categorical; 

LA level above upper 

limit of reference

values (2.28 mmol/L)

1 year after 

initiation of 

metformin

NR High

Sterner, 201237

Retrospective 

Sweden

Not funded

KQ 1a only

Diagnosis: ICD code 

or NR

eGFR using CKDEPI formula 

Age categories in 

years: 60-69, 70-79, 

80-89, ≥90

Median age 67 

years

Metformin: dose NR

No metformin: dose NR

Lactic acidosis 

measured by lactate 

levels >5mmol/L and 

serum pH <7.35

2 years NR High
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a Comparator applies only to KQ 1b.

Abbreviations: AFP = alpha-fetoprotein; BMI = body mass index; CHF = congestive heart failure; CKD = chronic kidney disease; eGFR = estimated glomerular 

filtration rate; HbA1c = glycated hemoglobin; ICD-9 = International Classification of Diseases-9; IQR = interquartile range; KQ = key question; LA = lactic 

acidosis; MACE = major adverse cardiac event; MELD = model for end-stage liver disease; Mod = moderate; NA = not applicable; NIAD = noninsulin antidiabetic 

drug; NR = not reported; Rx = prescription; T2D = type 2 diabetes
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Table 2. KQ 2 Study Characteristics by Condition

Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparator

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Chronic kidney 

disease (CKD)

Aguilar, 201141

Retrospective 

cohort, 

outpatient-based

USA

Government 

T2D: diagnosis, Rx

CKD: eGFR based 

on most recent 

serum creatinine

Metformin Rx 90 days 

pre-index to 30 days 

post-index date 

Dose NR

Comparator: no 

metformin Rx

All-cause mortality: 

time to death over 2 

year follow-up after 

index visit

Hazard ratio

2 years 

complete 

follow-up

No timeadjusted 

analysis

Propensity score 

matching

Low

Ekstrom, 201240

Retrospective 

cohort, 

population-based

Sweden 

Government

T2D: diagnosis, Rx

CKD: eGFR 

category (45-60, 30-

45)

12 months use of 

metformin

Median dose 1100-

1900mg 

Comparator: 12 

months continuous 

use or use of other 

oral antidiabetic agent

All-cause mortality: by 

death registry

MACE: diagnosis of

included conditions

Event rate, hazard 

ratio

Mean 3.9 years

No timeadjusted 

analysis

Age, sex, HbA1c, 

smoking, BMI, 

eGFR, 

comorbidities, 

medications

Mod

Masoudi, 200542

Retrospective

cohort, 

population-based

USA

Government

T2D: diagnosis by 

medical record, Rx

CKD: serum 

creatinine >1.5 

mg/dL

Metformin use after 

index hospitalization

Dose NR

Comp: no metformin 

or pioglitazone

All-cause mortality: 

time from index 

hospitalization to 

death or readmission 

for heart failure

MACE

Hazard ratio

Described as 1 

year

No timeadjusted 

analysis

Year, provider, 

hospital, baseline 

medical factors 

with p<0.05

Mod
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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparator

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Morgan, 201443

Retrospective 

cohort, 

population-based

UK

Industry

T2D: incident 

diagnosis based on 

codes and/or Rx

Hypoglycemia: NR

CKD: clinical 

diagnosis or 

baseline serum 

creatinine >132 or 

123 μmol/l (male, 

female)

New metformin Rx 

from medical records 

Dose NR

Comparator: new 

sulfonylurea Rx

All-cause mortality: 

determined by date of 

death in medical 

record 

Hazard ratio

Metformin: 2.9 

years

Sulfonylurea: 

3.1 years

No timeadjusted 

analysis

All baseline 

factors with 

difference, p<0.2 

Low

Roussel, 201044

Prospective 

cohort, 

outpatient-based

Multiple countries

Foundation, 

Industry 

T2D: Rx

CKD: eGFR based 

on baseline serum 

creatinine

Metformin use at 

baseline assessment

Dose NR

Comparator: no 

metformin use 

All-cause mortality: 

per 2-year follow-up 

assessment

Event rate, hazard 

ratio

Mean 20.8 and 

20.9 months for 

metformin 

users, 

nonusers

No timeadjusted 

analysis

All baseline 

factors with 

difference, p<0.2 

and propensity 

score

Mod

Weir, 201174

Nested casecontrol

Canada

Government 

T2D: ICD code and 

medical records

CKD: impaired 

eGFR based on 

serum creatinine 

values 

Metformin: given at all 

eGFR levels; dose NR

Comparator: Insulin, 

Glyburide: Dose NR

Hypoglycemia: by 

ICD-9 codes

Odds ratio

120-day 

interval 

immediately 

preceding 

index date to 

identify DM 

prescriptions

Hypoglycemic 

events, 

comorbidities,

recent 

hospitalization, 

medications, 

internist visits

Mod
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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparator

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Congestive heart 

failure (CHF)

Aguilar, 201141

Retrospective 

cohort, 

outpatient-based

USA

Government 

T2D: diagnosis 

and/or Rx for 

diabetes medication

CHF: diagnosis by 

ICD-9 codes

Metformin Rx 90 days 

pre-index to 30 days 

post-index date

Dose NR

Comparator: no 

metformin

All-cause mortality: 

time to death over 2 

years after index visit

MACE

Event rate, hazard 

ratio

2 years 

complete 

follow-up

No timeadjusted 

analysis

Propensity score 

matching

Low

Andersson, 

201025

Retrospective 

cohort, 

population-based

Denmark

Government 

T2D: Rx

CHF: first CHF 

hospitalization 

based on diagnostic 

codes

Metformin use based 

on Rx records

Dose NR

Comparator: multiple 

comparator arms

All-cause mortality: 

determined from death 

registry

MACE

Event rate, hazard 

ratio

Median 844 

days

Secondary 

time-adjusted 

analysis based 

on individual 

drug coverage

Year, age, sex, 

comorbidities, 

diabetes 

complications, 

medications

Mod

Eurich, 200526

Retrospective

cohort, 

population-based

Canada

Government, 

Foundation 

T2D: Rx for oral 

diabetes medication

CHF: First CHF 

hospitalization by 

ICD-9 codes

Metformin alone or in 

combination

Dose NR

Comp: sulfonylurea 

alone

All-cause mortality: 

method of 

determination NR at 1 

year and follow-up

MACE

Event rate, hazard 

ratio

Mean 2.5 years

Time 

adjustment not 

needed per 

design

CDS, number 

visits, 

medications, 

propensity score 

analysis

Mod
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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparator

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Evans, 201045

Retrospective 

cohort, 

population-based

Scotland

Foundation and 

private business 

T2D: diagnosis or 

Rx medication 1994-

2003 

CHF: first 

hospitalization with 

ICD codes

Rx for metformin or 

metformin + 

sulfonylurea

Dose NR

Comparator: 

sulfonylurea alone

All-cause mortality: by 

death certificate 

records

Odds ratio

Range: 1-9 

years (mean 

NR)

No timeadjusted 

analysis

All factors with 

univariate p<0.05

Mod

Inzucchi, 200546

Retrospective 

cohort

USA

Government

T2D: Clinician 

diagnosis, 

medication records

CHF: first CHF 

hospitalization 

based on diagnostic 

codes

 

Metformin alone or 

Metformin and 

Thiazolidinedione

Dose: NR

Comparator: No 

insulin sensitizer

Mortality: all-cause 

mortality with impaired 

LVEF, 1 year 

mortality, readmission 

for heart failure, MI.

MACE

Hazard ratio

Reported at 1 

year

Age, sex, race; 

cardiac and 

noncardiac 

comorbidities,

clinical 

characteristics at 

admission (eg, 

SBP), 

sample frame for 

index 

hospitalization

Low

Masoudi, 200542

Retrospective 

cohort, 

population-based

USA

Government 

T2D: diagnosis by 

medical record, Rx

CHF: ICD-9 codes 

at index 

hospitalization

Metformin use after 

index hospitalization

Dose NR

Comparator: no 

metformin

All-cause mortality: 

Medicare data (time 

from index date to 

death)

MACE

Hazard ratio

Reported as 1 

year, no mean

No timeadjusted 

analysis

Year, provider, 

hospital, baseline 

medical factors 

with difference, 

p<0.05

Mod
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparator

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Romero, 201335

Prospective 

cohort, 

community-based

Spain

Government 

T2D: diagnosis, Rx, 

laboratory values

CHF: Framingham 

criteria

Metformin use based 

on Rx records

Dose NR

Comparator: no 

metformin use (dose 

NR)

All-cause mortality: 

determined by medical 

records 

MACE

Event rate, hazard 

ratio

Median 56.9 

months

Time-adjusted 

analysis using 

person-years

Multivariate 

analysis

Low

Roussel, 201044

Prospective 

cohort, 

outpatient-based

Multiple countries

Foundation, 

Industry 

T2D: Rx

CHF: means of 

diagnosis unclear, 

likely clinical

Metformin use at 

baseline assessment

Dose NR

Comparator: no 

metformin use

All-cause mortality: 

per 2 year follow-up 

assessment

Event rate, hazard 

ratio

Mean 20.8 and 

20.9 months for 

metformin 

users, 

nonusers 

No timeadjusted 

analysis

All baseline 

factors with 

difference, p<0.2 

and propensity 

score

Mod

Shah, 201047

Retrospective 

cohort, 

outpatient-based

USA

Government,

Foundation 

T2D: diagnosis by 

clinician, medical 

record, self-report

CHF: diagnosis by

LVEF ≤40%

Metformin use at first 

visit 

Dose NR

Comparator: no 

metformin use

All-cause mortality: 

determined clinically 

(not including urgent 

heart transplant)

Follow-up at 1 

year and 2 

years 

No timeadjusted

analysis

Age, sex, LVEF, 

renal function, 

BMI, diabetes 

duration, 

medications

Mod
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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparator

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Tinetti, 201548

Retrospective 

cohort, 

population-based

USA

Government 

T2D: diagnosis by 

medical records

CHF: diagnosis by 

ICD-9 codes or 

claims data

Metformin Rx

 

Dose NR

Comparator: no 

metformin 

All-cause mortality: 

determined by 

Medicare vital status 

file

Hazard ratio

Median 24 

months

Time 

adjustment 

analysis

Age, sex, race, 

income, smoking, 

medication, 

insurance, 

physical and 

mental function

Mod

Weir, 201427

Retrospective 

cohort, 

population-based 

USA

NR 

T2D: Rx for oral 

diabetes medication

Hypoglycemia: NR 

CHF: First CHF 

hospitalization by 

ICD-9 codes

Exposure to metformin 

based on pharmacy 

claims within 90 days 

of index event

Mean dose NR

Comparator: no 

exposure to metformin

All-cause mortality: 

U.S. national death 

index files 

Event rate, odds ratio

Median 1.4 

years

Partial time 

adjustment

Propensity score 

analysis

Mod

Liver disease

Ampuero, 201249

Retrospective 

cohort

Spain

Government 

T2D: by clinician

Liver biopsy-proven 

cirrhosis with 

additional clinical 

evaluation

Metformin treatment

Dose: 0, 20, 50, 100 

and 200 mmol/L

Comparator: no

metformin 

All-cause mortality: 

overall survival rate 

trend; categorical

Metformin: 39.6 

± 28.3 months 

Comparator: 

45.5 ± 26.5 

months

Yes Mod
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Study

Design

Country

Funding

Condition 

Definitions

Metformin Use

Dose

Comparator

Outcome Definition

Reporting

Exposure 

Duration

Statistical 

Adjustment ROB

Nkontchou, 

201150

Prospective 

cohort

France

NR

T2D: Rx, laboratory 

values

Liver disease: 

1. Biopsy-proven 

cirrhosis with 

additional clinical 

evaluation

2. Presence of antiHCV antibodies

3. Presence of 

serum HCV RNA

Metformin treatment

Dose NR

Comparator: no 

metformin

All-cause mortality: 

liver-related death; 

categorical

Median followup of 5.7 years 

(range 3.8-9.5)

Age, platelet 

count, BMI, 

alcohol abuse, 

diabetes duration

High

Zhang, 201438

Retrospective 

cohort, 

population-based

USA

Government, 

Foundation 

T2D: by clinician, 

Rx, self-report, or 

laboratory values

Liver biopsy-proven 

cirrhosis with 

additional clinical 

evaluation)

Continuation or 

discontinuation of 

metformin after 

cirrhosis (defined as 

cessation of metformin 

within 3 months after 

diagnosis)

Dose NR

Comparator: 

discontinued 

metformin use

LA: categorical

All-cause mortality: 

10-year survival; 

categorical

5-10 years Age, sex, albumin, 

MELD score, AFP 

level, etiology of 

cirrhosis

Low

Abbreviations: AFP = alpha-fetoprotein; BMI = body mass index; CHF = congestive heart failure; CKD = chronic kidney disease; eGFR = estimated glomerular 

filtration rate; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; LA = lactic acidosis; LVEF = left ventricular ejection fraction; MACE = major adverse 

cardiac event; MELD = model for end-stage liver disease; NA = not applicable; NR = not reported; RNA = ribonucleic acid; Rx = prescription; T2D = type 2 

diabetes
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

79

APPENDIX G. RESULTS FOR OLDER ADULTS BY STUDY DESIGN

KQ 2 Older Adults—Study Characteristics of RCTs

Study

Country

Funding

T2D Condition

Age in Years (N)

Other Precautions 

Excluded

Metformin Dose

Comparator Dose

Outcome Definition

Reporting

Exposure 

Duration ROB

Blonde, 200251

USA

Industry

Diagnosis by clinician, 

laboratory value (A1c

remains ≥7.4% with diet, 

exercise, sulfonylurea) 

≥65 subgroup (134)

Liver disease, renal 

disease, heart failure

Metformin: 500-2000mg 

Glibenclamide: 2.5mg or 

5.0mg

A1c: laboratory value

Hypoglycemia: blood 

sugar <60 mg/dl

16 weeks Low

Cryer, 200552

USA

Industry

Diagnosis by clinician

(“suboptimal control” on 

diet or sulfonylurea) 

≥65

Abnormal renal or 

liver function

Metformin: 500-2500mg

Usual care: any 

nonmetformin 

medication

LA: medical record

MACE: medical 

record

Mortality: medical 

record

1 year Mod

Garber, 200253

USA

Industry

Diagnosis by clinician, 

laboratory value (A1c 

remains >7% with diet, 

exercise)

≥65 subgroup (159)

Abnormal renal, liver 

function

Metformin: 500-2000mg 

Glibenclamide: 2.5mg or 

5.0 mg

A1c: laboratory value

Hypoglycemia: 

glucose <50 mg/dl or 

<100 if on metformin

20 weeks Low

Gregorio,199954

Italy

NR

Diagnosis by clinician

(A1c remains ≥9% with 

sulfonylurea) 

>70 (174)

Abnormal liver 

function, respiratory 

or heart failure, 

Creatinine >1 or 

CrCl<100 ml/min/m2

Metformin: NR

 

Sulfonylurea: increased 

dose (exact dose NR)

Weight: clinical scale

A1c, LDL, HDL, total 

cholesterol: 

laboratory values

18 months High
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

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Study

Country

Funding

T2D Condition

Age in Years (N)

Other Precautions 

Excluded

Metformin Dose

Comparator Dose

Outcome Definition

Reporting

Exposure 

Duration ROB

Hanefeld,

200455

Europe, Canada

Foundation, 

Industry

Diagnosis by clinician, 

laboratory value (A1c 

remains 7.55-11% on 

sulfonylurea) 

>65 subgroup (212)

History of MI, TIA, or 

stroke in prior 6 

months; symptomatic 

CHF

Metformin + 

sulfonylurea: 500-

2500mg/dl

Pioglitazone + 

sulfonylurea: NR

Weight: clinical scale

A1c, LDL, 

hypoglycemia: 

laboratory value

52 weeks Low

Marre, 200256

Europe

Industry

Diagnosis by laboratory 

value (FPG ≥126 on 

metformin, diet & 

exercise) 

≥65 subgroup (130)

Renal disease, 

hepatic dysfunction, 

severe respiratory 

disease, acute heart 

failure, MI

Metformin: 500-2000mg 

Glibenclamide: 2.5mg or 

5.0 mg

A1c: laboratory value

Hypoglycemia:

glucose <50 mg/dl or 

<100 if on metformin 

16 weeks Low

Schweizer,

200957

Americas, Asia, 

Europe

Industry

Diagnosis by clinician 

plus

laboratory value (A1c 

7%-9% off 

hypoglycemic) 

≥65 (335)

CHF requiring 

medication; liver 

disease, renal 

disease

Metformin: 500-1500mg 

Vildagliptin: 100mg 

A1c: laboratory value

Hypoglycemia: 

glucose <60 mg/dL

24 weeks Low

Abbreviations: A1c = glycated hemoglobin; CHF = congestive heart failure; FPG = fasting plasma glucose; HDL = high-density lipoprotein; LA = lactic acidosis; 

LDL = low-density lipoprotein; MACE = major adverse cardiac event; MI = myocardial infarction; NR = not reported; Rx = prescription; T2D = type 2 diabetes; 

TIA = transient ischemic attack
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

81

KQ 2 Older Adults—Study Characteristics of Observational Studies

Study

Design

Country

Funding

T2D Condition

Exclusions 

Age in Years (N)

Metformin Dose

Comparator Dose Outcome Exposure 

Duration

Statistical 

Adjustment ROB

Bodmer, 200859

Nested case 

control 

UK

Industry

Oral Rx

Exclusions: T1D

≥70 (50,048)

Metformin: NR

Sulfonylurea: NR

LA, 

hypoglycemia 

leading to 

emergency 

department visit 

or death

NR Use of 

sulfonylureas, other 

oral antidiabetic 

medications, insulin, 

BMI, smoking,

comorbidities, other 

medications

Low

Bannister, 201458

Retrospective 

cohort 

UK

Industry

Diagnosis by clinician

Exclusions: None

>70 (90,463) 

Metformin: NR

Sulfonylurea: NR

All-cause 

mortality

Mean 2.8 years Age, comorbidity 

index, sex, smoking 

status, medications

Mod

Huizinga, 201060

Retrospective 

cohort

USA

Government

Oral Rx

Exclusions: CHF, 

CKD, liver disease

 

65-75, >75 years

(2096-2484)

Metformin: NR

Sulfonylurea: NR

A1c, BMI 1 year Age, sex, race, BMI, 

medications, 

outpatient visits, 

hospitalizations, 

psychiatric 

comorbidities

Mod

Leung, 201061

Prospective cohort 

Canada

NR

Diagnosis by clinician 

Exclusions: NR 

67-91 (20)

Metformin: NR

No metformin

Vitamin B12 3 months None High
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82

Study

Design

Country

Funding

T2D Condition

Exclusions 

Age in Years (N)

Metformin Dose

Comparator Dose Outcome Exposure 

Duration

Statistical 

Adjustment ROB

Roumie, 201262

Retrospective 

cohort 

USA

Government

Diagnosis by ICD 

code, Rx, laboratory 

values

Exclusions: None

≥65 (253,690)

Metformin: NR

Sulfonylurea: NR

Acute MI, stroke 

or death

Acute MI or 

stroke

Metformin: median 

0.78 years 

Sulfonylurea: 

median 0.61 years

Age, sex, race, 

HbA1c/other clinical 

variables, health 

care utilization, 

smoking, 

medications, 

comorbidities

Low

Tzoulaki, 200964

Retrospective 

cohort 

UK

Not funded

T2DM: diagnosis by 

ICD code

Exclusion: patients 

not taking oral 

antidiabetic drugs, or 

patients taking insulin

>65 (91,521)

Metformin: NR

Sulfonylurea: NR

Thiazolidinedione: NR

MACE; mortality Metformin: median: 

5.59 years

Sulfonylurea: 

median 8.5 years

(first generation),

6.6 years (second 

generation)

Thiazolidinedione: 

median 6.7 years

Sex, BMI, smoking 

SBP, other 

laboratory variables 

(eg, HbA1c), 

duration of diabetes, 

stratified by year 

and age quartiles at 

treatment; 

comorbidities, other 

medications, 

complications from 

diabetes

Low

Wang, 201463

USA 

Government

Retrospective 

cohort

Diagnosis by ICD 

code for T2D and oral 

Rx

Exclusions: CKD, liver 

disease

65-90 (2415)

Metformin: NR

Sulfonylurea: NR

All-cause 

mortality

≥24 weeks Age, race/ethnicity, 

diabetes duration, 

comorbidity score, 

statin use, smoking, 

BMI, LDL, A1c

Mod

Abbreviations: BMI = body mass index; CHF = congestive heart failure; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HbA1c = 

glycated hemoglobin; ICD-9 = International Classification of Diseases-9; LA = lactic acidosis; LDL = low-density lipoprotein; MACE = major adverse cardiac 

event; Mod = moderate; NR = not reported; Rx = prescription; SBP = systolic blood pressure; T1D- type 1 diabetes; T2D = type 2 diabetes
Metformin Use in Patients with Contraindications or Precautions Evidence-based Synthesis Program

ERRATA AND CORRECTIONS 

Page 1, paragraph titled “Data Sources and Searches”

Formerly: “We searched MEDLINE (via PubMed), the Cochrane Central Register of Controlled 

Trials (KQ 2 only), Embase, and the International Pharmaceutical Abstracts.” 

Now: “We searched MEDLINE (via PubMed), the Cochrane Central Register of Controlled 

Trials (KQ 2 only), Embase, the International Pharmaceutical Abstracts, and ClinicalTrials.gov.” 

Page 9, paragraph titled “Search Strategy” 

Added: “We also searched ClinicalTrials.gov for relevant completed and ongoing studies.” 

Page 12, final paragraph

Changed: Guideline for Knapp-Hartung correction from n<10 to n<20. Guideline was applied to 

all analyses; no results changed.

Page 14, final paragraph

Added: “Of note, we identified no ongoing studies meeting our inclusion criteria in 

ClinicalTrials.gov.” 

Page 23, final paragraph

Formerly: “The other study did find a significantly lower likelihood of congestive heart failure 

readmission among metformin users versus nonusers (n = 5859, HR 0.91, 95% CI 0.84-0.99).” 

Now: “The other study found that metformin use was significantly associated with slightly lower 

CHF readmission (n = 5859, HR 0.91, 95% CI 0.84-0.99).” 

Page 24, paragraph titled “All-cause Mortality” 

Correction: “[...] 13,390 patients with CHF” to “[...] 13, 930 patients with CHF.” 

Page 26, figure 4

Updated forest plot to reflect number correction from Masoudi 2005 (see page 24 correction, 

above). MA results did not change when data was corrected.