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Original Research
Assessment of Serum Creatinine and Kidney Function among IncidentMetformin Users
Melissa Schorr BSc a,b, Brenda R. Hemmelgarn MD, PhD, FRCPC a,c, Marcello Tonelli MD, SM, FRCPC d,Andrea Soo MSc c, Braden J. Manns MD, MSc, FRCPC a,c, Lauren C. Bresee PhD a,*,for the Alberta Kidney Disease Networka Department of Medicine, University of Calgary, Calgary, Alberta, Canadab Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Irelandc Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canadad Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
a r t i c l e i n f o
Article history:
Received 7 December 2012
Received in revised form
9 May 2013
Accepted 13 May 2013
Keywords:
diabetes
estimated glomerular filtration rate
metformin
serum creatinine
Mots cls :
diabte
estimation du dbit de filtration
glomrulaire
metformine
cratinine srique
a b s t r a c t
Objective: Metformin is considered the first-line antihyperglycemic therapy for type 2 diabetes, but
should be used with caution in people with renal insufficiency. Our study objective was to describe the
proportion of patients who have an assessment of kidney function (serum creatinine [SCr] and estimated
glomerular filtration rate [eGFR]) around the time of initiation of metformin in new users.
Methods: We used data from the Alberta Kidney Disease Network to identify patients with diabetes (age,
66 y) with a new prescription for metformin from November 1, 2002, to March 31, 2008. We assessed
whether SCr measurement was completed before and after metformin initiation. The eGFR was calcu-
lated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and categorized
into CKD stages. Frequency of metformin use based on SCr measurement and CKD stage was reported
using descriptive statistics.
Results: A total of 22 051 subjects were identified as new metformin users. Overall, 25.4% (n5608) had
no measurement of SCr or assessment of eGFR before metformin prescription. In addition, of patients
with an eGFR measurement, 38.7% (n8544) of individuals had an eGFR of less than 60 mL/min/1.73 m2.
Conclusions: One quarter of patients started on metformin did not have a SCr measurement completed
beforehand. Also, metformin was used commonly among patients with diabetes and CKD, potentially
putting these individuals at risk for adverse events.
2013 Canadian Diabetes Association
r s u m
Objectif : La metformine est considre comme le traitement antihyperglycmique de premire intention
contre le diabte de type 2, mais elle devrait tre utilise avec prudence chez les personnes ayant une
insuffisance rnale. Lobjectif de notre tude tait de dcrire la proportion de patients qui avaient eu une
valuation du fonctionnement rnal (cratinine srique [SCr] et une estimation du dbit de filtration
glomrulaire [eDFG]) aux alentours de lintroduction de la metformine chez les nouveaux utilisateurs.
Mthodes : Nous avons utilis les donnes du Alberta Kidney Disease Network pour identifier les patients
ayant le diabte ( 66 y) qui avaient eu une nouvelle ordonnance de metformine entre le 1 er novembre
2002 et le 31 mars 2008. Nous avons valu si la mesure de la SCr avait t effectue avant et aprslintroduction de la metformine. LeDFG avait t calcule laide de lquation CKDEPI (Chronic Kidney
Disease Epidemiology Collaboration) et classe en stades de CKD (o CKD signifie chronic kidney disease,
soit linsuffisance rnale chronique). La frquence de lutilisation de la metformine selon la mesure de la
SCr et le stade de CKD avait t rapporte au moyen des statistiques descriptives.
Rsultats : Un total de 22 051 sujets avaient t identifis comme de nouveaux utilisateurs de metfor-
mine. Dans lensemble, 25,4 % (n 5608) navaient eu aucune mesure de la SCr ou dvaluation de leDFG
avant lordonnance de metformine. De plus, parmi les patients ayant une mesure de l eDFG, 38,7 % (n
8544) des individus avaient une eDFG de moins de 60 ml/min/1,73 m 2.
* Address for correspondence: Lauren C. Bresee, PhD, Department of Medicine,
University of Calgary, 3280 Hospital Dr NW, Calgary, Alberta T2N 4Z6, Canada.
E-mail address: [email protected].
Contents lists available at SciVerse ScienceDirect
Canadian Journal of Diabetesj o u r n a l h o m e p a g e :
w w w . c a n a d i a n j o u r n a l o f d i a b e t e s . c o m
1499-2671/$ e see front matter 2013 Canadian Diabetes Association
http://dx.doi.org/10.1016/j.jcjd.2013.05.002
Can J Diabetes 37 (2013) 226e230
mailto:[email protected]://www.sciencedirect.com/science/journal/14992671http://www.canadianjournalofdiabetes.com/http://dx.doi.org/10.1016/j.jcjd.2013.05.002http://dx.doi.org/10.1016/j.jcjd.2013.05.002http://dx.doi.org/10.1016/j.jcjd.2013.05.002http://dx.doi.org/10.1016/j.jcjd.2013.05.002http://dx.doi.org/10.1016/j.jcjd.2013.05.002http://dx.doi.org/10.1016/j.jcjd.2013.05.002http://www.canadianjournalofdiabetes.com/http://www.sciencedirect.com/science/journal/14992671mailto:[email protected] -
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Conclusions : Un quart des patients qui prenaient de la metformine navaient pas eu de mesure de la SCr
au pralable. De plus, la metformine avait frquemment t utilise chez les patients ayant le diabte et
une NPC, exposant potentiellement ces individus un risque dvnements indsirables.
2013 Canadian Diabetes Association
Introduction
Metformin is a biguanide that acts primarily on the liver to
reduce gluconeogenesis, thereby decreasing blood glucose levels in
people with type 2 diabetes (1). Metformin is an effective anti-
hyperglycemic agent and has been shown to reduce deaths related
to diabetes and diabetes-related endpoints significantly (2,3). As a
result, Canadian and international guidelines recommend metfor-
min as a first-line therapy for the treatment of hyperglycemia in
people with type 2 diabetes (4e6).
When prescribed in people with an estimated glomerular
filtration rate (eGFR) of 60 mL/min/1.73 m2 or higher, the inci-
dence of lactic acidosis in those patients taking metformin is
exceedingly rare, and is estimated to be 4.3 cases per 100,000
patient years (7). However, decreased kidney function results in
metformin accumulation and subsequent increases in lactatethrough the conversion of glucose to lactate and inhibition of
lactate use by the liver in gluconeogenesis (1,7,8). Albeit contro-
versial, metformin thus is listed as being contraindicated in pa-
tients with impaired kidney function (creatinine clearance
[CrCl]
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Measurement of cohort characteristics
Sex, age and Aboriginal status were identified from the Alberta
Health and Wellness Population Registry database (14). We used
Statistics Canada 2001 and 2006 census data to identify income
quintiles and rural or urban residency based on census data closest
to the index date (15). A diagnosis of hypertension was determined
based on previously validated criteria (25). We also included the
median number of general practitioner visits after the study index
date and other comorbid conditions within 3 years before the indexdate using the Deyo adaptation (International Classification of
Diseases, 9th revision, Clinical Modification) and the Quan valida-
tion (International Classification of Diseases, 10th revision) of the
Charlson comorbidity index (26,27).
Statistical analyses
Descriptive statistics were used to compare baseline character-
istics of incident metformin users, stratified by both frequency of
SCr measurements (never,
-
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no prior assessment of their kidney function. In addition, among
those who had an SCr measurement, 30.7% had an eGFR of less than
60 mL/min/m2, which indicates that a significant number of peopletaking metformin at the very least require close monitoring of their
kidney function (9). Despite this, we found that those with an eGFR
of less than 45 mL/min/1.73 m2, who are recommended to have
their kidney function measured every 3 months (9), equivalent to
4 tests per year, had a median of 2 SCr measurements in the year
after metformin initiation. Prescriptions for metformin despite
contraindications seemed to be common; in a study by Holstein
et al (12), 73% of the study population had at least one contrain-
dication to metformin therapy, and the results of this study have
been confirmed by other studies (11,13). In addition, individuals
with an eGFR of less than 30 mL/min/1.73 m2 were more likely to
have other comorbidities including congestive heart failure and
chronic obstructive pulmonary disease compared with individuals
with an eGFR of greater than 60 mL/min/1.73 m2, putting them atgreater risk for adverse events such as lactic acidosis. Our results
indicate that a significant number of people with reduced kidney
function who are taking metformin are not having their kidney
function adequately monitored (9). Although the relationship be-
tween metformin and lactic acidosis is unclear, it remains prudent
at this time to monitor kidney function closely in patients with
reduced kidney function who are taking metformin to avoid
development of serious adverse events (9).
As with most studies that use administrative data, our study had
limitations. We only were able to evaluate metformin users age
66 years and older and, therefore, it is unclear whether our results
are generalizable to those age 65 years and younger. In addition, we
were unable to assess whether patients were advised by their
physicians to have their SCr measured but did not; we only were
able to evaluate the frequency of SCr measurement. However, this
should not take away from our results because it is the physician s
choice to initiate metformin, and metformin was started in 8.0% ofpatients without any SCr measurement as well as in 17.4% of
patients without a pre-metformin SCr measurement. Also, we were
unable to identify the dosage of metformin received by each person
or the prescriber of metformin (e.g. general practitioner or endo-
crinologist), and therefore we were unable to identify whether
people had dosage changes relating to their kidney function. We do
not believe this impacted our results, however, because all in-
dividuals initiating metformin should have their kidney function
assessed, regardless of type of prescriber or the dose of metformin
the patient is receiving. Finally, given that there is no validated
measure for identifying lactic acidosis from administrative data, we
were unable to evaluate whether use of metformin in patients with
decreasing renal function was associated with an increased risk of
lactic acidosis.In this large, population-based study of people 66 years of age
and older with diabetes, we found that new use of metformin
without prior SCr measurement was common. In addition, among
those with a SCr measurement, use of metformin was common
among patients with an eGFR of less than 60 mL/min/1.73 m2, in
whom close monitoring of kidney function is necessary.
Author Disclosures
The authors have no conflicts of interest to disclose. MS
researched data and wrote the manuscript; BH developed the study
question and reviewed and edited the manuscript; MT reviewed
and edited the manuscript; AS conducted the study analyses; BM
reviewed and edited the manuscript; and LB developed the study
Table 2
Baseline characteristics of the study population, by stage of chronic kidney disease
Characteristic 60 mL/min/1.73 m2,
n13 507 (61.3%)
CKD stage 3a
(45e59.9 mL/min/1.73 m2),
n4444 (20.1%)
CKD stage 3b
(30e44.9 mL/min/1.73 m2),
n1898 (8.6%)
CKD stages 4 and 5
(29.9 mL/min/1.73 m2),
n436 (2.0%)
p value
Mean age, y (SD) 73.4 (5.62) 76.7 (6.55) 78.7 (6.93) 80.0 (6.93)
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question, wrote the manuscript and reviewed/edited the manu-
script. LB serves as the guarantor for this study and takes
responsibility for the contents of the manuscript. This work was
supported by an interdisciplinary team grant from Alberta
InnovateseHealth Solutions. Dr. Bresee was supported by the 4th
International Conference on Preventive Cardiology/Heart and
Stroke Foundation of Canada/Canadian Cardiovascular Society
(ICPC/HSFC/CCS) Fellowship in Preventive Cardiology and a
fellowship award from Alberta InnovateseHealth Solutions.
Drs. Hemmelgarn, Tonelli and Manns were supported by careerawards from Alberta InnovateseHealth Solutions and by a joint
initiative between Alberta Health and Wellness and the Univer-
sities of Alberta and Calgary. Dr. Hemmelgarn was supported by the
Roy and Vi Baay Chair in Kidney Research. Dr. Tonelli was supported
by a Government of Canada Research Chair. Ms. Soo was supported
by an Alberta InnovateseHealth Solutions studentship award.
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