Can J Diabetes 37 (2013) 226e230

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Canadian Journal of Diabetes

journal homepage: www.canadianjournalofdiabetes.com

Original Research

Assessment of Serum Creatinine and Kidney Function among Incident Metformin 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 Network
a

Department of Medicine, University of Calgary, Calgary, Alberta, Canada Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland c Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada d Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
b

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 ltration rate metformin serum creatinine

a b s t r a c t
Objective: Metformin is considered the rst-line antihyperglycemic therapy for type 2 diabetes, but should be used with caution in people with renal insufciency. Our study objective was to describe the proportion of patients who have an assessment of kidney function (serum creatinine [SCr] and estimated glomerular ltration 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 calculated 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 identied 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
Mots cls : diabte estimation du dbit de ltration glomrulaire metformine cratinine srique

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 insufsance 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 ltration 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 identier les patients ayant le diabte ( 66 y) qui avaient eu une nouvelle ordonnance de metformine entre le 1er novembre 2002 et le 31 mars 2008. Nous avons valu si la mesure de la SCr avait t effectue avant et aprs lintroduction de la metformine. LeDFG avait t calcule laide de lquation CKDEPI (Chronic Kidney Disease Epidemiology Collaboration) et classe en stades de CKD (o CKD signie chronic kidney disease, soit linsufsance 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 identis comme de nouveaux utilisateurs de metformine. 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 leDFG, 38,7 % (n 8544) des individus avaient une eDFG de moins de 60 ml/min/1,73 m2.

* 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: lauren.bresee@albertahealthservices.ca. 1499-2671/$ e see front matter 2013 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2013.05.002

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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 antihyperglycemic agent and has been shown to reduce deaths related to diabetes and diabetes-related endpoints signicantly (2,3). As a result, Canadian and international guidelines recommend metformin as a rst-line therapy for the treatment of hyperglycemia in people with type 2 diabetes (4e6). When prescribed in people with an estimated glomerular ltration rate (eGFR) of 60 mL/min/1.73 m2 or higher, the incidence 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 lactate through the conversion of glucose to lactate and inhibition of lactate use by the liver in gluconeogenesis (1,7,8). Albeit controversial, metformin thus is listed as being contraindicated in patients with impaired kidney function (creatinine clearance [CrCl] <60 mL/min/1.73 m2, or serum creatinine [SCr] level 136 mmol/L in males or 124 mmol/L in females) or when kidney function is unknown because of its perceived potential to cause lactic acidosis (8). This recommendation is not without controversy, however, and more recently it has been recommended that renal function be monitored closely (every 3 months) when using metformin in patients with an eGFR/CrCl of 30 to 60 mL/min/ 1.73 m2, and is contraindicated in patients with an eGFR/CrCl less than 30 mL/min/1.73 m2 (4,9). Diabetes is a well-known risk factor for nephropathy (4), and more than 30% of people with diabetes have chronic kidney disease (CKD) (10). Although studies that have evaluated the use of metformin in people with reduced kidney function exist, these studies were limited by small study numbers and an early time period of study (e.g. 1993 to 1995), making results less applicable to current clinical practice (11e13). As a result, we aimed to describe the proportion of incident users of metformin who underwent serum creatinine measurements in the period before and 1 year after initiation of metformin therapy in a large, recent population-based cohort.

residents 65 y) (14). These data are complete from 1995 onward (14). Patients with kidney transplant or on chronic dialysis were identied from the Alberta Renal Program databases (16).

Identication of the study cohort: incident metformin users in people with diabetes We rst identied individuals with diabetes based on the established case denition of the National Diabetes Surveillance System (17). We then selected incident metformin users, dened as individuals with diabetes, aged 66 years and older (for a 1-year look-back period because universal drug coverage starts at age 65 in the province of Alberta), with at least 1 dispensation of metformin and no prior dispensation of metformin in the previous year. The index date was the date of the rst prescription of metformin. Because our study database did not have the duration of prescriptions available, we calculated cumulative drug exposure to metformin for the 365 days including and after the index date, stratied based on stage of kidney disease. Cumulative drug exposure was calculated based on the following formula: metformin strength * quantity of metformin dispensed/dened daily dose of metformin (2000 mg) (18,19). People with a kidney transplant or on chronic dialysis before or on the study index date were excluded. We also excluded patients from 2 of the health regions who did not have laboratory data available for the 6-month period before cohort entry.

Identication of SCr measurements and calculation of eGFR SCr measurements were obtained from the AKDN laboratory database. Outpatient SCr was the preferential measure, however, if this measurement was unavailable then in-patient or emergency department SCr values were used. We evaluated the proportion of individuals who had at least 1 SCr measurement in the 6 months before the study index date, and within 1 year after the index date was evaluated for all subjects, compared with no measurements. The SCr closest to the index date was used to calculate the eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (20). We used the CKD-EPI equation to calculate eGFR because it more accurately predicts GFR relative to the Modication of Diet in Renal Disease study equation and the Cockcroft-Gault equation, and has been validated across a number of populations (20e22). Lastly, the Canadian Diabetes Association 2008 and 2013 guidelines include both creatinine clearance and eGFR interchangeably for assessing kidney function in patients taking metformin (4,23). Kidney function was categorized based on CKD stage: eGFR of 60 mL/min/1.73 m2 or greater stage 3a (eGFR, 45 to 59.9 mL/min/ 1.73 m2), stage 3b (30 to 44.9 mL/min/1.73 m2), stages 4 and 5 (eGFR  29.9 mL/min/1.73 m2) (24), and unknown (patients without an SCr measurement in the study period). We chose these cutoff values given their established CKD stage denition, as well as the recommendations in the literature regarding monitoring of kidney function in people taking metformin in those with an eGFR of 30 to 60 mL/min/1.73 m2, and contraindicated in those with an eGFR of less than 30 mL/min/1.73 m2 (9,24).

Methods Study design and data sources This was a population-based cohort study. Information from the databases of the Alberta Kidney Disease Network (AKDN) (14) was used to form the study cohort from November 1, 2002, until March 31, 2008, with follow-up evaluation until March 31, 2009, ensuring a minimum of 1 year of follow-up evaluation. The databases of the AKDN include laboratory data from May 2002 on adult residents of Alberta, a Canadian province of approximately 3.3 million people (14,15). The AKDN databases also include demographic and vital status information from the Alberta Health and Wellness Population Registry database, as well as information from the Physician Claims, Hospitalization, Ambulatory Care and Alberta Blue Cross drug databases (the latter is complete for

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Measurement of cohort characteristics Sex, age and Aboriginal status were identied 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 index date using the Deyo adaptation (International Classication of Diseases, 9th revision, Clinical Modication) and the Quan validation (International Classication of Diseases, 10th revision) of the Charlson comorbidity index (26,27). Statistical analyses Descriptive statistics were used to compare baseline characteristics of incident metformin users, stratied by both frequency of SCr measurements (never, <6 months before initiation of metformin, <12 months after initiation, or both before and after metformin initiation) and stage of CKD. We used omnibus chi-squared testing to compare proportions, omnibus analysis of variance to compare means, and the omnibus Kruskal-Wallis test to compare medians across each category. SAS version 9.2 (SAS Institute, Cary, NC) was used for the analysis. Ethics approval Permission to conduct this study was granted from the Conjoint Health Research Ethics Board at the University of Calgary. Results A total of 22 051 people with diabetes who were new users of metformin were included in this study. Of these individuals, 13 841

(62.8%) had at least 1 SCr measurement both before and after metformin initiation, 2602 (11.8%) had only a pre-metformin measurement, 3842 (17.4%) had only a post-metformin measurement, and 1766 (8.0%) had no SCr measurements completed before or after the initiation of metformin (Table 1). Demographic and clinical characteristics were similar across groups, stratied by frequency of SCr measurements. Metformin users without SCr measurements were more likely to reside in a rural location (31.3%) relative to those who had both pre-metformin and post-metformin measurements (15.8%) (p<0.001). People who used metformin and had both pre-metformin initiation and post-metformin initiation SCr measurements were signicantly more likely to have all comorbidities evaluated than those with either pre- or post- or no measurements (p0.002 to <0.001). Baseline characteristics of the study cohort, by stage of CKD, are presented in Table 2. A total of 13 507 (61.3%) participants had an eGFR of 60 mL/min/1.73 m2 or higher, 4444 (20.1%) had an eGFR of 45 to 59 mL/min/1.73 m2 (stage 3a), 1898 (8.6%) had an eGFR of 30 to 44 mL/min/1.73 m2 (stage 3b), and 436 (2.0%) had an eGFR of 29 mL/min/1.73 m2 or less (stages 4 and 5). Metformin users with stages 4 and 5 CKD were more likely to be female, older, and had a longer duration of diabetes compared with people with an eGFR of 60 mL/min/1.73 m2 or greater (p<0.001). Reduced eGFR was associated with a higher prevalence of comorbidities including hypertension, cerebrovascular disease, heart failure and chronic obstructive pulmonary disease (p<0.001); users with no measures of eGFR had the lowest number of comorbidities (Table 2). Finally, the median number of serum creatinine measurements in the index year was 2 for those with an eGFR of less than 60 mL/min/ 1.73 m2 (Table 2). Discussion Although metformin use is contraindicated in patients with an unknown level of kidney function or a CrCl of less than 60 mL/min (10), we found that 25.4% of people starting metformin therapy had

Table 1 Baseline characteristics of the study cohort stratied by timing of serum creatinine (SCr) measurement Characteristics No SCr measurement, n1766 (8.0%) 1 SCr 6 months before, and including, the index date; no SCr measurement 1 year after index date, n2602 (11.8%) 74.1 (6.0) 1370 (52.7%) 68 (2.6%) 24 589 634 496 458 401 454 466 1922 493 160 27 6 1911 189 222 506 18 4 (0.9%) (22.6%) (24.4%) (19.1) (17.6%) (15.4%) (17.5%) (2e1961) (73.8%) (19.0%) (6.2%) (1.0%) (3e9) (73.4%) (7.3%) (8.5%) (19.5%) (0.7%) (0.2%) No SCr measurement 6 months before, and including, the index date; 1 SCr measurement 1 year after index date, n3842 (17.4%) 74.2 (6.2) 2009 (52.3%) 97 (2.5%) 75 859 814 763 734 597 812 737.5 2660 768 319 95 8 2652 223 315 715 34 2 (3.2%) (22.4%) (21.2%) (19.9%) (19.1%) (15.5%) (21.1%) (4e2417) (69.2%) (20.0%) (8.3%) (2.5%) (5e12) (69.0%) (5.8%) (8.2%) (18.6%) (0.9%) (0.1%) 1 SCr 6 months before, and including, the index date and 1 SCr measurement 1 year after index date, n13 841 (62.8%) 75.0 (6.4) 7164 (51.8%) 280 (2.0%) 182 3253 3151 2694 2427 2134 2181 625 8925 3183 1419 314 9 11144 1434 2361 3590 198 45 (1.3%) (23.5%) (22.8%) (19.5%) (17.5%) (15.4%) (15.8%) (5e2340) (64.5%) (23.0%) (10.3%) (2.2%) (5e14) (80.5%) (10.4%) (17.1%) (26%) (1.4%) (0.3%) <0.001 <0.001 <0.001 <0.001 <0.001 0.002 p value

Mean age, y (SD) Male Aboriginal Income quintile Missing 1 (lowest) 2 3 4 5 (highest) Rural residence Median duration of diabetes, d (IQR) CKD stage 60 mL/min/1.73 m2 3a (45e59.9 mL/min/1.73 m2) 3b (30e44.9 mL/min/1.73 m2) 4 and 5 (29.9 mL/min/1.73 m2) Median GP visits 1 year after index date, (25th and 75th percentiles) Hypertension Cerebrovascular disease CHF COPD Mild liver disease Moderate to severe liver disease

74.1 (6.2) 903 (51.1%) 43 (2.4%) 56 409 415 308 327 251 552 802.5 Not Not Not Not (3.2%) (23.2%) (23.5%) (17.4%) (18.5%) (14.2%) (31.3%) (8e2282)

<0.001 0.72 0.10 <0.001

<0.001 <0.001 <0.001

applicable applicable applicable applicable 6 (4e10) (71.0%) (5.2%) (8.5%) (18.7%) (0.6%) (0%)

1253 92 150 331 11 0

CKD, chronic kidney disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; GP, general practitioner; IQR, interquartile range.

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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%) 73.4 (5.62) 7569 (56.0%) 329 (2.4%) 166 3115 3066 2604 2387 2169 2285 598 (1.2%) (23.1%) (22.7%) (19.3%) (17.7%) (16.1%) (16.9%) (4e2203) CKD stage 3a (45e59.9 mL/min/1.73 m2), n4444 (20.1%) 76.7 (6.55) 2089 (47.0%) 65 (1.5%) 71 1004 1013 890 841 625 714 624 (1.6%) (22.6%) (22.8%) (20.0%) (18.9%) (14.1%) (16.1%) (4e2376) CKD stage 3b (30e44.9 mL/min/1.73 m2), n1898 (8.6%) 78.7 (6.93) 721 (38.0%) 41 (2.2%) 34 463 421 378 310 292 352 721 (1.8%) (24.4%) (22.2%) (19.9%) (16.3%) (15.4%) (18.6%) (6e2840) CKD stages 4 and 5 (29.9 mL/min/1.73 m2), n436 (2.0%) 80.0 (6.93) 164 (37.6%) 10 (2.3%) 10 119 99 81 81 46 96 1258 (2.3%) (27.3%) (22.7%) (18.6%) (18.6%) (10.6%) (22.0%) (22e3159) p value

Mean age, y (SD) Male Aboriginal Income quintile Missing 1 (lowest) 2 3 4 5 (highest) Rural residence Median duration of diabetes, d (25th and 75th percentiles) >8 GP visits within 1 year after index date Hypertension Cerebrovascular disease CHF COPD Mild liver disease Moderate to severe liver disease Median number of metformin prescriptions in index year (25th and 75th percentiles) Median cumulative drug exposure of metformin in the year after initiation (25th and 75th percentiles) Median frequency of monitoring of SCr in index year (25th and 75th percentiles)

<0.001 <0.001 0.002 0.001

0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.34 0.13 <0.001

7189 (53.2%) 9911 1023 1324 2992 155 27 5.0 (73.4%) (7.6%) (9.8%) (22.2%) (1.2%) (0.2%) (3.0e6.0)

2555 (57.5%) 3722 477 847 1116 58 18 5.0 (83.8%) (10.7%) (19.1%) (25.1%) (1.3%) (0.4%) (3.0e6.0)

1137 (59.9%) 1683 275 532 556 30 5 5.0 (88.7%) (14.5%) (28.0%) (29.3%) (1.6%) (0.3%) (3.0e7.0)

249 (57.1%) 391 71 195 147 7 1 4.0 (89.7%) (16.3%) (44.7%) (33.7%) (1.6%) (0.2%) (1.0e7.0)

180.0 (97.5e260.0)

160.0 (88.75e245.0)

150.0 (75.0e236.25)

95.0 (33.75e198.0)

<0.0001

1.0 (1.0e2.0)

2.0 (1.0e3.0)

2.0 (1.0e4.0)

2.0 (1.0e5.0)

<0.001

CKD, chronic kidney disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; GP, general practitioner; SCr, serum creatinine.

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 signicant number of people taking 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 contraindication to metformin therapy, and the results of this study have been conrmed 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 at greater risk for adverse events such as lactic acidosis. Our results indicate that a signicant number of people with reduced kidney function who are taking metformin are not having their kidney function adequately monitored (9). Although the relationship between 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 physicians choice to initiate metformin, and metformin was started in 8.0% of patients 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 endocrinologist), 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 individuals 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 conicts 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

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question, wrote the manuscript and reviewed/edited the manuscript. 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 career awards from Alberta InnovateseHealth Solutions and by a joint initiative between Alberta Health and Wellness and the Universities 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. References
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