459544

2012

DVD12510.1177/1474651412459544The British Journal of Diabetes and Vascular DiseaseVolume XX Issue X. XX / XX XXXX

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Renal function in a large cohort of metformin treated patients with type 2 diabetes mellitus
GUNNAR STerner1, SLVE ElmsTHl2, ANDERS Frid3
Abstract
Objectives To survey renal function in a defined population on metformin treatment. Methods All patients in the city of Malm who collected at least three prescriptions of metformin during two years were identified from a central registry at the National Board of Health and Welfare in Sweden. Estimated glomerular filtration rate (eGFR), from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, of 5,408 patients were compared with a control population (n=2,815) from the same town. All cases of severe lactic acidosis leading to intensive care unit admission were also sought. Results In patients >79 years of age, 38% and 12% of patients had a best recorded eGFR registered below 60 and 45 ml/ min/1.73 m2 respectively. In the age group 7079 years the corresponding figures were 16% and 3% respectively. The eGFR was significantly higher in metformin treated patients than in control subjects in each age group. Three cases of lactic acidosis were recorded during the 2-year period studied. No patient with lactic acidosis was found in the highest age group. Conclusions In spite of reduced and fluctuating GFR in elderly patients, treatment with metformin is feasible. Adjusting the dose of metformin to renal function and adequately informing the patient could enable continuous treatment in moderately reduced GFR. Br J Diabetes Vasc Dis 2012;12:227-231. Key words: CKD-EPI, diabetes mellitus, GFR, glomerular filtration rate, lactic acidosis, metformin
1 Departments

Abbreviations and acronyms CKD-EPI Chronic Kidney Disease Epidemiology Collaboration eGFR estimated glomerular filtration rate GS Good Ageing in Skne GFR glomerular filtration rate ICD10  International Statistical Classification of Diseases and Related Health Problems 10th revision ICU intensive care unit IDMS isotope dilution mass spectrometry MDRD modification of diet in renal disease NICE National Institute for Health and Clinical Excellence PCr plasma creatinine SNAC Swedish National study on Ageing and Care

Introduction
Metformin is considered first line pharmacological treatment for type 2 diabetes mellitus and has been shown to be associated with lowered cardiovascular morbidity and mortality than other treatments.1,2 Metformin seldom causes hypoglycaemia and has favourable effects on body weight.3 Lactic acidosis is an infrequent but severe complication associated with metformin treatment.4 Metformin is a non-protein bound, water-soluble molecule and is eliminated exclusively through renal excretion. In patients with normal renal function 90% of the drug is excreted within 12 hours and the plasma half life after oral administration is 26 hours.5 When renal function declines half life is prolonged and serum levels of metformin may increase.6 Due to the risk of lactic acidosis, which carries a severe prognosis, metformin dose should be reduced as GFR declines and treatment stopped in severe renal failure. Metformin is not nephrotoxic but could accumulate in severe chronic or acute renal insufficiency leading to increased risk for lactic acidosis. Other conditions, like acute or chronic heart failure, septicaemia and liver disease, could also lead to lactic acidosis rendering metformin treatment inappropriate in these situations.7 We have earlier demonstrated that down to a stable GFR of 30 ml/ min/1.73 m2 metformin levels in serum only increase marginally and are still less than one tenth of serum levels found in patients with metformin-associated lactic acidosis.8 Renal function based only on plasma creatinine is an uncertain way of estimating GFR and an unreliable guide for the dosing of metformin.
DOI: 10.1177/1474651412459544227

of Nephrology and Transplantation, Skane University Hospital, Malm, Sweden. 2Geriatric Medicine, Skane University Hospital, Malm, Sweden. 3Endocrinology, Lund University, Skane University Hospital, Malm, Sweden. Corresponding author: Dr. Gunnar Sterner Department of Nephrology and Transplantation, Skane University Hospital, Malm, Sweden. Tel: +46 (0)7688 71005; Fax +46 (0)4033 7052 E-mail: gunnar.sterner@skane.se

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Table 1. EGFR (CKD-EPI) in groups stratified by age in metformin treated and controls (eGFR was calculated from the lowest available creatinine value)

Age category

Controls (excluding diabetes) Metformin group Controls Metformin Controls Metformin Controls Metformin Controls Metformin Controls Metformin

Mean

Standard deviation

Significance of comparison between controls and metformin-treated

Group 1 (< 60 years) Group 2 (6069 years) Group 3 (7079 years) Group 4 (8089 years) Group 5 ( 90 years)

1,505 1,244 1,648 490 1,445 652 744 203 66 77.4 86.9 66.1 76.5 55.9 65.7 49.6 62.1 14.2 13.9 14.6 15.3 15.6 15.9 15.2 15.3

p<0.001 p<0.001 p<0.001 p<0.001

Key: CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate.

GFR calculated from plasma creatinine using validated equations (eGFR) is considered a more appropriate way to evaluate renal function and has been adopted in several guidelines.9,10 We evaluated eGFR in a large, geographically well defined population on metformin treatment.

Materials and methods Subjects

Using a central registry at the National Board of Health and Welfare in Sweden all patients prescribed metformin in the city of Malm (population 293,909 on 31 December 2009) were identified. Patients who filled at least three prescriptions during 1 January 2008 to 31 December 2009 were identified. The available registry did not enable information on the metformin dose. At least one PCr result was retrospectively collected from 5,408 patients by direct linkage to the laboratory database at the university hospital, the only laboratory serving the entire area. In the patient group 54.4% were men; median age was 67 years (range 1798) and eGFR (ml/min/1.73 m) was calculated using the CKD-EPI formula.11 The highest and lowest eGFRs were determined and the patients were stratified by age into five groups: (1) <60; (2) 6069; (3) 7079; (4) 8089 and (5) >90. Groups 25 were compared with a control population from the GS project which is part of the SNAC, a published, population-based cohort study.12 The control subjects consisted of 2,815 elderly people from the same population, median age 73 years (range 6093): 219 of these subjects with diabetes mellitus and seven with incomplete information were excluded.

a Hitachi modular P analysis system (Roche, Basel, Switzerland, application 652) for the controls. The methods employed calibration traceable to a common reference material including a zero-point calibrator13,14 and were as such also traceable to IDMS. Total analytical variation for both analyses (coefficient of variance) was 1.43.0% at concentrations of creatinine between 60 and 578 mol/L. The lowest and highest PCr registered during the two years was used to calculate GFR (using the CKD-EPI equation)11. In the GFR prediction equation PCr was expressed in mol/L, age in years, body weight in kg, height in cm and eGFR in ml/ min/1.73 m2 body surface area.

Lactic acidosis
All medical records at the ICU of the University Hospital were searched for the diagnosis of diabetes or acidosis (E10*, E11*, E14* and E872 according to ICD10) during the period 20082009. One hospital with one ICU serves the whole city of Malm and thus all cases requiring intensive care were identified. Lactic acidosis was defined by lactate levels > 5 mmol/L and serum pH < 7.35.

Statistics
Subjects were categorised into age groups and difference between mean values of eGFR (CKD-EPI) for the metformin treated groups and the control groups was tested with twotailed independent t-test.

Ethical considerations Laboratory analyses

PCr results were determined by a modified Jaffe colorimetric method on a Beckman LX20 analyser (Beckman Coulter Inc., Fullerton, CA, USA) for the patients and the same method on
228

All information from the central registry at the National Board of Health and Welfare and from the local chemical laboratory were encoded. Thus no personal information regarding the included patients was available to the investigators. The study
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Table 2. Distribution of best eGFR (CKD-EPI) in the different age groups in patients treated with metformin during the study period. The two highest age groups are merged into one.

was approved by the regional ethical review board in Lund. The study number in clinicaltrials.gov is NCT01358994.

Group 1 (< 60 years) n Best GFR < 60 ml/min/ 1.73 m2 (%) < 45 (%) < 30 (%) Reduction > 25 (%) >50 (%) 1,505

Group 2 (6069 years) 1,648

Group 3 (7079 years) 1,445

Groups 4+5 ( 80 years) 810

Results
Table 1 presents the 5,408 patients stratified by age in comparison with control subjects. EGFR calculated from the CKDEPI equation was significantly higher in patients treated with metformin in all groups irrespective of age, compared with controls. The distribution of eGFR as well as the variation of renal function during the two years in patients treated with metformin is shown in table 2. In the highest age group, patients above 79 years, best eGFR was < 60 ml/min/1.73 m2 in 38% and < 45 ml/min/1.73 m2 in 12% of the patients. In the age group 7079 years the corresponding figures were 16% and 3% respectively. In the group > 79 years of age, 32% and 8% of the patients showed a > 25% and > 50% reduction of eGFR respectively at any time during the two years studied. For patients between 70 and 79 years the corresponding figures were 23% and 4.6%. Table 3 shows the number and percentage of patients with a lowest registered eGFR under 30 ml/min/1.73 m2 during the two years. Of patients above the age of 79 years 9% had an eGFR below 30 ml/min/1.73 m2 at some time during the study period. Three cases of lactic acidosis associated with the use of metformin were identified in this population of approximately 300,000 inhabitants during two years. In one case eGFR was 41 ml/min/1.73 m2 before the acidosis, in another case eGFR was > 90 and unknown in another case. None of the patients was over 79 years of age. Further clinical details on the three cases of lactic acidosis are presented in table 4. One patient was diagnosed with pancreatic cancer and liver metastasis. The clinical history of the other two cases revealed no heart or liver disease or any ischaemic tissue injury predisposing for lactic acidosis. Both patients normalised their PCr at follow-up suggesting an acute renal injury causing accumulation of metformin.

0.5 0 0 8 1.1

5 1 0.06 14 2.4

16 3 0.3 23 4.6

38 12 0.7 32 8

Key: CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate.

Table 3. Metformin treated patients with a lowest eGFR below 30 ml/min/ 1.73 m2 during the study period. A total number of at least 179 patients have been at acute risk of developing lactic acidosis due to renal failure.

Age group

Patients with eGFR <30 ml/min/1.73 m2 n (%) 8 (0.5) 30 (2) 67 (5) 74 (9)

< 60 6069 7079 80

Key: eGFR = estimated glomerular filtration rate.

Table 4. Clinical data on the three cases with lactic acidosis identified during two years

Sex

Age

PCr previous mol/L unknown 103 89

PCr admission mol/L 819 676 675

PCr follow-up mol/L 82 96 ---

pH admission 6.68 6.77 6.69

Lactate admission mmol/L 25.0 23.0 29.0

s-metformin admission mol/L unknown 415 unknown

Metformin dose mg/day 3000 2500 2000(?)

Outcome

F M F

65 73 75

Discharged full health Discharged full health Death 2nd day. Autopsy: cancer of pancreas, multiple metastasis

Key: PCr = plasma creatinine

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Discussion
There is evidence for an association between elevated plasma levels of metformin and risk of lactic acidosis although this relationship has been questioned.15 The development of lactic acidosis demonstrated in cases intoxicated intentionally with metformin argue however for a causal link.16,17 It is reasonable to believe that a gradual fall of renal function will eventually raise plasma metformin to danger levels in patients with diabetes mellitus on treatment. The present study, covering all patients in a middle-sized Swedish town, allowed us to evaluate the highest and the lowest eGFR during the study period. The data show that a considerable number of elderly patients on metformin demonstrate both reduced and variable eGFR. In total, 74 patients (9%) aged > 79 years had an eGFR < 30 ml/min/1.73 m2 at some point during the observation period and could thus be considered at risk of developing lactic acidosis. Yet only three cases were found, none in this age group. We believe all cases of severe lactic acidosis during the 2-year period were located, although we cannot exclude mild cases being undetected. Metformin was given to approximately 2% of the population of a mid-sized Swedish town, Malm, and thus is one of the most frequently prescribed drug treatments in the elderly. As metformin is eliminated only via the renal route, reduced renal excretory function will give rise to higher metformin plasma levels. The mechanisms by which metformin may increase blood lactate in the blood could include increased anaerobic glycolysis, reduced gluconeogenesis from lactate, decreased lactate oxidation and accelerated conversion of pyruvate to both lactate and acetyl CoA.18 The inadequacy of using plasma creatinine as a marker of renal function has been emphasised for a long time. Due to dependency on muscular mass and tubular secretion creatinine is unreliable as a marker of GFR especially in older people and early in the course of renal disease.19 Instead estimation of GFR using equations based on anthropometric data and plasma creatinine or cystatin C are now generally recommended.11 A new creatinine-based equation known as the CKD-EPI equation was recently proposed.11 The formula, using the same variables as the modified MDRD formula, has been shown to improve diagnostic accuracy especially at higher GFR. Our data using eGFR show that in elderly metformin-treated patients with type 2 diabetes almost 40% have an eGFR < 60 ml/min/1.73 m2 as their best value during the two-year study period. Kennedy et al.20 found that 1317% of a large population of metformin treated patients demonstrated an eGFR < 60 mL/min/1.73 m2, although frequency according to age was not given. This level is in many countries, Sweden among them, considered the lower threshold for metformin treatment. Furthermore eGFR varies with time and this variation seems more marked in the elderly. One third of the patients in the oldest age group showed a 25% decrease of eGFR during the period studied indicating that the elderly are more prone to renal shut down due to various factors, acute illness probably being the most common.

Based on our findings that in clinical practice metformin is being used in a large number of patients with low GFR and the incidence of lactic acidosis still remains very low, we suggest the continued use of this treatment when renal function is moderately reduced and stable. Earlier reports on the incidence of lactic acidosis have demonstrated low risk.5 It is generally recommended that metformin dose is reduced or stopped at low GFR although no consensus has been reached. After consulting the European Medicines Agency and the US Food and Drug Administration the Medical Products Agency in Sweden recommended that metformin should be stopped when GFR (CockcroftGault) goes below 60 ml/min/1.73 m2.21 This means that a high portion of elderly patients would have to switch to other treatments. NICE in the UK advises dose reduction at 45 ml/min/1.73 m2 and 30 ml/min/1.73 m2 as the eGFR (MDRD) threshold where the drug should be stopped.22 Based on an extensive literature survey Lipska et al. have come to a similar conclusion.23 We have reported that patients on metformin with GFR > 30 ml/min/1.73 m2 show serum levels < 20 mol/L which in our (unsubstantiated) opinion are safe.8 Patients with lactic acidosis associated with metformin were found to have serum levels above 250 mol/L. Metformin clearance is higher than glomerular filtration rate indicating a substantial component of tubular secretion.6 This probably explains why metformin serum levels only increase slightly in spite of falling GFR. Only in severe renal failure will serum metformin increase to high levels which augment the risk for lactic acidosis substantially. The low risk of developing lactic acidosis, especially in the older age groups with moderately reduced and pendulous renal function, as demonstrated here, support this assumption. As shown in table 3 at least 179 patients had renal failure, stage 4 or worse, at some point during the study, but we do not know in how many of these instances metformin was discontinued. On the other hand patients with already lowered kidney function could be more prone to acute renal failure, thus patients in the highest age group could be at risk. All patients on metformin treatment must bear in mind that treatment should be stopped whenever fluid intake is reduced or gastrointestinal losses increased. Provision of this information to the patients seems to be more essential than substituting the drug at the first sign of renal impairment. Our experience confirms that lactic acidosis nearly always develops as a result of an acute severe impairment of renal function, such as in connection with a gastroenteritis or dehydration in combination with various drug treatments. In the present study we noted that patients on metformin had slightly higher eGFR than controls subjects, which may indicate selection of patients for metformin treatment, such as that patients with creatinine rise are excluded from treatment. We support a dose reduction of metformin in patients already at eGFR < 60 ml/min/1.73 m and certainly at eGFR < 45 ml/ min/1.73 m as recommended by NICE in the UK. The dose should be lowered from 2,0003,000 mg daily to 5001,000 mg as eGFR falls below 45 ml/min/1.73 m. In selected cases serum concentrations of metformin could be useful.
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Key messages
Metformin may be used with care and frequent mon-

itoring in moderate renal disease, reducing dose if required Metformin should not be used in severe renal disease

In conclusion we have demonstrated that although many elderly patients on metformin have reduced renal function, some with an eGFR < 30 mL/min/1.73 m2, and a considerable variation of eGFR over time, the incidence of lactic acidosis remains low. We believe that adjusting metformin dose to renal function is more important than abandoning treatment when GFR has declined. In some cases avoid treatment in the highest age group and stop treatment where fluid intake is affected or gastronintestinal losses are increased. With this approach an effective treatment at a low cost could be offered to the majority of patients with type 2 diabetes mellitus.

Acknowledgements
G.S. researched data, contributed to discussion, wrote and edited the manuscript. A.F. researched data, contributed to discussion and edited the manuscript. S.E. made statistical calculations, contributed to discussion and reviewed the manuscript.

Funding
This work received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

References
1. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012;55:1577-96. 2. Holman RR, Paul SK, Bethel MA et al. 10 years follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89. 3. Bolen S, Feldman L, Vassy J et al. Systematic review: Comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007;147:386-99.

4. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9. 5. Bailey CJ, Campbell IW, Chan C (eds). Metformin. The gold standard. Chichester: Wiley, 2007;228. 6. Sirtori CR, Franceschini G, Galli-Kienle M et al. Disposition of met formin (N,N-dimetylbiguanide) in man. Clin Pharmacol Ther 1978;24: 683-93. 7. Funk GC, Doberer D, Kneidinger N et al. Acidbase distrurbances in critically ill patients with cirrhosis. Liver Int 2007;27:901-9. 8. Frid A, Sterner G, Lndahl M et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function. Diabetes Care 2010;33:1291-3. 9. National Kidney Foundation. KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. New York: National Kidney Foundation, 2002. 10. Brosius FC, Hostetter TH, Kelepouris E et al. Detection of chronic kidney disease in patients with or at increased risk of cardiovascular disease: a science advisory from the American Heart Association Kidney And Cardiovascular Disease Council; the Councils on High Blood Pressure Research, Cardiovascular Disease in the Young, and Epidemiology and Prevention; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: developed in collaboration with the National Kidney Foundation. Circulation 2006;114:1083-7. 11. Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12. 12. Ekstrm H, Elmsthl S. Restriction in social participation and lower life satisfaction among fractured in pain. Results from the population study Good Ageing in Skne. Arch Gerontol Geriatr 2008;46: 409-24. 13. Mrtensson A, Rustad P, Lund H, Ossowicki H. Creatinine reference intervals for corrected methods. Scand J Clin Lab Invest 2004;64: 439-41. 14. Rustad P, Felding P, Franzson L et al. The NordicReference Interval Project 2000: recommended reference intervals for 25 commonbiochemical properties. Scand J Clin Lab Invest 2004;64:271-8. 15. Philbrick AM, Ernst ME, McDanel DL et al. Metformin use in renal dysfunction: Is a serum creatinine threshold appropriate? Am J Health Syst Pharm 2009;66:2017-23. 16. Lacher M, Hermanns-Clausen M, Haeffner K et al. Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 2005;164:362-5. 17. Guo PYF, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial 2006;19:80-3. 18. Dunn CJ, Peters DH. Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs 1995;49:721-49. 19. Duncan L, Heathcote J, Djurdjev O, Levin A. Screening for renal disease using serum creatinine: who are we missing? Nephrol Dial Transplant 2001;16:1042-6. 20. Kennedy L, Herman WH. Renal status among patients using metformin in a primary care setting. Diabetes Care 2005;28:922-4. 21. Medical Products Agency Sweden. Recommended pharmacological treatment on diabetes. Uppsala: Information from Medical Products Agency Sweden 2010:1. 22. NICE. The management of type 2 diabetes. London, National Institute for Health and Clinical Excellence, 2009;13-14. 23. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34: 1431-7.

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