investigación original evaluación de la creatinina sérica y la función renal entre los...

7/29/2019 Investigacin original Evaluacin de la creatinina srica y la funcin renal entre los incidentes usuarios Metformina

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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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