Metformin Use in Type 2 Diabetes Mellitus With CKD: Is It Time to Liberalize Dosing Recommendations?
2015; Elsevier BV; Volume: 66; Issue: 2 Linguagem: Inglês
10.1053/j.ajkd.2015.04.001
ISSN1523-6838
Autores Tópico(s)Diabetes Management and Research
ResumoCommentary on Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-2675.Metformin is a very effective drug for type 2 diabetes mellitus (T2DM) with relatively few side effects1Rojas L.B. Gomes M.B. Metformin: an old but still the best treatment for type 2 diabetes.Diabetol Metab Syndr. 2013; 5: 6Crossref PubMed Scopus (342) Google Scholar and has other potential benefits, such as lowering of cardiovascular risk2Ekstrom N. Schioler L. Svensson A.M. et al.Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register.BMJ Open. 2012; 2Crossref Scopus (175) Google Scholar, 3Lamanna C. Monami M. Marchionni N. Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials.Diabetes Obes Metab. 2011; 13: 221-228Crossref PubMed Scopus (287) Google Scholar and possible lowering of cancer risk.4Quinn B.J. Kitagawa H. Memmott R.M. Gills J.J. Dennis P.A. Repositioning metformin for cancer prevention and treatment.Trends Endocrinol Metab. 2013; 24: 469-480Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar However, there is concern that metformin may increase the risk of lactic acidosis in people with chronic kidney disease (CKD). Considering the number of people with CKD and T2DM,5Centers for Disease Control. Diabetes: successes and opportunities for population-based prevention and control. At A Glance 2011. http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm. Accessed February 21, 2015.Google Scholar, 6US Renal Data System. Chronic kidney disease (CKD) in the United States. 2014. http://www.usrds.org/2014/view/Default.aspx. Accessed February 21, 2015.Google Scholar there are potentially millions of people who are not currently taking metformin who might benefit from this medication. In a recent issue of the Journal of the American Medical Association, Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar address the important issue of whether metformin increases the risk of lactic acidosis in people with CKD.What does this important study show?Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar reviewed published studies from January 1950 through June 2014 to determine the risk of metformin-associated lactic acidosis in patients with T2DM and CKD. They found 818 articles using the search terms “metformin, kidney, renal, chronic kidney disease, lactic acidosis, and glomerular filtration rate” in major online databases and selected 65 to include in this review based on extensive exclusion criteria. Their analysis revealed that lactate level was often normal in patients taking metformin with mild (creatinine clearance of 60-90 mL/min) to moderate CKD (creatinine clearance of 30-60 mL/min). In studies in which metformin use was associated with increased lactate level, none increased to the level of overt lactic acidosis (defined as lactate level > 5 mmol/L and pH < 7.35). In the reported cases of lactic acidosis, there were other associated causes such as infection, liver failure, acute kidney injury (AKI), or cardiovascular collapse. Metformin use was concomitant but not clearly causative. The rate of lactic acidosis in patients taking metformin was the same as the rate of lactic acidosis in people with T2DM who did not take metformin.Given these results, the authors suggest the following. For estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2, use a maximal daily dose of 2,550 mg of metformin; for eGFR of 45 to 59 mL/min/1.73 m2, use no more than 2,000 mg of metformin per day; and for eGFR of 30 to 44 mL/min/1.73 m2, use no more than 1,000 mg per day. The authors further suggest that metformin therapy should not be initiated in patients with eGFRs < 45 mL/min/1.73 m2 and advise against using metformin in patients with eGFRs < 30 mL/min/1.73 m2. The significant strengths of this study in comparison to previous studies are that the authors reviewed published articles that comprised the entire history of metformin use, focused on studies specifically directed at patients with decreased kidney function, and reviewed an extensive number of relevant articles. The potential weaknesses are inherent to all retrospective studies: the conclusions depend on the validity of the selected studies, there may be selection bias for the articles ultimately evaluated based on preexisting hypotheses, interpretation of the selected articles may be affected by preexisting hypotheses, and the methods used to analyze the articles will affect the conclusions.How does this study compare with prior studies?Lu et al8Lu W.R. Defilippi J. Braun A. Unleash metformin: reconsideration of the contraindication in patients with renal impairment.Ann Pharmacother. 2013; 47: 1488-1497Crossref PubMed Scopus (30) Google Scholar performed a similar online database search covering the period from 1950 to August 2013, but limited their review to 6 articles, all of which were included in the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar article. In this smaller article set, Lu et al8Lu W.R. Defilippi J. Braun A. Unleash metformin: reconsideration of the contraindication in patients with renal impairment.Ann Pharmacother. 2013; 47: 1488-1497Crossref PubMed Scopus (30) Google Scholar reached the same conclusions as Inzucchi et al.7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar Most of the other previous studies are included in the analysis conducted by Inzucchi et al.7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar Salpeter et al9Salpeter S.R. Greyber E. Pasternak G.A. Salpeter E.E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.Cochrane Database Syst Rev. 2010; 14: CD002967Google Scholar evaluated 347 comparative trials and cohort studies in a systematic review and noted that no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use were observed. There was no difference in lactate levels in individuals treated with metformin versus nonmetformin therapies. This analysis did not specifically focus on patients with CKD, but the authors included studies evaluating people with CKD in their analysis.Other relevant studies were based on analyses of patient databases. Ekstrom et al2Ekstrom N. Schioler L. Svensson A.M. et al.Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register.BMJ Open. 2012; 2Crossref Scopus (175) Google Scholar evaluated 51,675 patients from Sweden’s National Registries. No increased risk of metformin-associated lactic acidosis was seen in any group, including patients with CKD. Rather, the authors reported that metformin use was associated with reduced risk of cardiovascular disease, acidosis/serious infection, and all-cause mortality compared with insulin and reduced risk of all-cause mortality compared with other oral hypoglycemic agents.Bodmer et al10Bodmer M. Meier C. Krahenbuhl S. Jick S.S. Meier C.R. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis.Diabetes Care. 2008; 31: 2086-2091Crossref PubMed Scopus (347) Google Scholar analyzed the UK-based General Practice Research Database. In the study population of 50,048 patients with T2DM, 6 cases of lactic acidosis were identified. No difference between metformin and other oral hypoglycemic agents was observed. The authors concluded that lactic acidosis was very rare and was associated with concurrent comorbid conditions.In contrast, a recent report by Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar showed a different result. They evaluated the same database that Bodmer et al10Bodmer M. Meier C. Krahenbuhl S. Jick S.S. Meier C.R. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis.Diabetes Care. 2008; 31: 2086-2091Crossref PubMed Scopus (347) Google Scholar analyzed except that Bodmer et al evaluated patient data from 1994 to 2005, whereas Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar studied the period from 2004 to 2012. They found an increased risk for lactic acidosis in patients using metformin with eGFRs < 60 mL/min. This risk was further increased in patients with decreased eGFRs taking >730 g per year of metformin (>2 g/d). Thus, they concluded that metformin risk for lactic acidosis was both dose and GFR dependent. Published in the same issue of Diabetes Care, Richy et al12Richy F.F. Sabido-Espin M. Guedes S. Corvino F.A. Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study.Diabetes Care. 2014; 37: 2291-2295Crossref PubMed Scopus (74) Google Scholar analyzed the same database from 2007 to 2012. They found very low lactic acidosis event rates that increased with decreased kidney function; however, reflecting the very low rates, they concluded that these differences were not clinically significant.12Richy F.F. Sabido-Espin M. Guedes S. Corvino F.A. Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study.Diabetes Care. 2014; 37: 2291-2295Crossref PubMed Scopus (74) Google Scholar The different conclusions from these 3 studies using the same database are likely due to variable methods used to analyze the data and varying ascertainment periods.Taken together, these findings suggest that it is reasonable to liberalize the dosing recommendations. Other countries have already changed their recommendations. For example, Canadian and Australian guidelines recommend using metformin with caution and reducing the metformin dose when eGFR is 30 to 60 mL/min/1.73 m2. Both guidelines recommend discontinuing metformin therapy when eGFR is 90 mL/min, holding the drug 1 day before a procedure will lead to an ∼90% decrease in drug level.16Bristol Meyers Squibb. Glucophage [package insert]. 2015. http://packageinserts.bms.com/pi/pi_glucophage_xr.pdf. Accessed February 21, 2015.Google Scholar At lower GFRs, there is decreased clearance; thus, holding the drug therapy 2 or 3 days before a procedure might be indicated in people with lower GFRs.4.Is there a risk using metformin in combination with medications that lower GFR (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, etc)? There are very few data about this question, but it appears prudent to follow up individual patients’ eGFRs and decrease metformin dose or hold the dose based on the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar recommendations for dosing based on eGFR.5.How often do eGFRs need to be monitored in individuals treated with metformin? eGFR should be assessed every 3 to 6 months depending on baseline eGFR, stability of eGFR, other medications, and chronic comorbid conditions and more frequently during acute medical events.6.Is there an upper age limit for using metformin? This is unclear, but data suggest that adjusting the dose for eGFR is also the best approach.Current data clearly show that the risk for metformin-associated lactic acidosis is low. Even in the Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar study, in which an increased risk for metformin-associated lactic acidosis with decreased GFR was reported, event rates were very low (21 events/126,881 person-years of metformin use in patients with GFRs < 60 mL/min and 29/547,731 for patients with GFRs > 60 mL/min). Hence, even in individuals with stage 3 CKD, the absolute risk of metformin-associated lactic acidosis is low.17Lalau J.D. Arnouts P. Sharif A. De Broe M.E. Metformin and other antidiabetic agents in renal failure patients.Kidney Int. 2015; 87: 308-322Crossref PubMed Scopus (89) Google ScholarIn conclusion, the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar study provides further support for changing the metformin dosing recommendations in the United States, as has already been done in Canada13Booth G. Cheng A.Y. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Methods.Can J Diabetes. 2013; 37: S61-S68Google Scholar and Australia.14The Royal Australian College of General Practitioners. General practice management of type 2 diabetes. 2014-2015. http://www.racgp.org.au/your-practice/guidelines/diabetes/. Accessed February 22, 2015.Google Scholar Commentary on Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-2675. Commentary on Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-2675. Commentary on Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-2675. Metformin is a very effective drug for type 2 diabetes mellitus (T2DM) with relatively few side effects1Rojas L.B. Gomes M.B. Metformin: an old but still the best treatment for type 2 diabetes.Diabetol Metab Syndr. 2013; 5: 6Crossref PubMed Scopus (342) Google Scholar and has other potential benefits, such as lowering of cardiovascular risk2Ekstrom N. Schioler L. Svensson A.M. et al.Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register.BMJ Open. 2012; 2Crossref Scopus (175) Google Scholar, 3Lamanna C. Monami M. Marchionni N. Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials.Diabetes Obes Metab. 2011; 13: 221-228Crossref PubMed Scopus (287) Google Scholar and possible lowering of cancer risk.4Quinn B.J. Kitagawa H. Memmott R.M. Gills J.J. Dennis P.A. Repositioning metformin for cancer prevention and treatment.Trends Endocrinol Metab. 2013; 24: 469-480Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar However, there is concern that metformin may increase the risk of lactic acidosis in people with chronic kidney disease (CKD). Considering the number of people with CKD and T2DM,5Centers for Disease Control. Diabetes: successes and opportunities for population-based prevention and control. At A Glance 2011. http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm. Accessed February 21, 2015.Google Scholar, 6US Renal Data System. Chronic kidney disease (CKD) in the United States. 2014. http://www.usrds.org/2014/view/Default.aspx. Accessed February 21, 2015.Google Scholar there are potentially millions of people who are not currently taking metformin who might benefit from this medication. In a recent issue of the Journal of the American Medical Association, Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar address the important issue of whether metformin increases the risk of lactic acidosis in people with CKD. What does this important study show?Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar reviewed published studies from January 1950 through June 2014 to determine the risk of metformin-associated lactic acidosis in patients with T2DM and CKD. They found 818 articles using the search terms “metformin, kidney, renal, chronic kidney disease, lactic acidosis, and glomerular filtration rate” in major online databases and selected 65 to include in this review based on extensive exclusion criteria. Their analysis revealed that lactate level was often normal in patients taking metformin with mild (creatinine clearance of 60-90 mL/min) to moderate CKD (creatinine clearance of 30-60 mL/min). In studies in which metformin use was associated with increased lactate level, none increased to the level of overt lactic acidosis (defined as lactate level > 5 mmol/L and pH < 7.35). In the reported cases of lactic acidosis, there were other associated causes such as infection, liver failure, acute kidney injury (AKI), or cardiovascular collapse. Metformin use was concomitant but not clearly causative. The rate of lactic acidosis in patients taking metformin was the same as the rate of lactic acidosis in people with T2DM who did not take metformin.Given these results, the authors suggest the following. For estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2, use a maximal daily dose of 2,550 mg of metformin; for eGFR of 45 to 59 mL/min/1.73 m2, use no more than 2,000 mg of metformin per day; and for eGFR of 30 to 44 mL/min/1.73 m2, use no more than 1,000 mg per day. The authors further suggest that metformin therapy should not be initiated in patients with eGFRs < 45 mL/min/1.73 m2 and advise against using metformin in patients with eGFRs < 30 mL/min/1.73 m2. The significant strengths of this study in comparison to previous studies are that the authors reviewed published articles that comprised the entire history of metformin use, focused on studies specifically directed at patients with decreased kidney function, and reviewed an extensive number of relevant articles. The potential weaknesses are inherent to all retrospective studies: the conclusions depend on the validity of the selected studies, there may be selection bias for the articles ultimately evaluated based on preexisting hypotheses, interpretation of the selected articles may be affected by preexisting hypotheses, and the methods used to analyze the articles will affect the conclusions. Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar reviewed published studies from January 1950 through June 2014 to determine the risk of metformin-associated lactic acidosis in patients with T2DM and CKD. They found 818 articles using the search terms “metformin, kidney, renal, chronic kidney disease, lactic acidosis, and glomerular filtration rate” in major online databases and selected 65 to include in this review based on extensive exclusion criteria. Their analysis revealed that lactate level was often normal in patients taking metformin with mild (creatinine clearance of 60-90 mL/min) to moderate CKD (creatinine clearance of 30-60 mL/min). In studies in which metformin use was associated with increased lactate level, none increased to the level of overt lactic acidosis (defined as lactate level > 5 mmol/L and pH < 7.35). In the reported cases of lactic acidosis, there were other associated causes such as infection, liver failure, acute kidney injury (AKI), or cardiovascular collapse. Metformin use was concomitant but not clearly causative. The rate of lactic acidosis in patients taking metformin was the same as the rate of lactic acidosis in people with T2DM who did not take metformin. Given these results, the authors suggest the following. For estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2, use a maximal daily dose of 2,550 mg of metformin; for eGFR of 45 to 59 mL/min/1.73 m2, use no more than 2,000 mg of metformin per day; and for eGFR of 30 to 44 mL/min/1.73 m2, use no more than 1,000 mg per day. The authors further suggest that metformin therapy should not be initiated in patients with eGFRs < 45 mL/min/1.73 m2 and advise against using metformin in patients with eGFRs < 30 mL/min/1.73 m2. The significant strengths of this study in comparison to previous studies are that the authors reviewed published articles that comprised the entire history of metformin use, focused on studies specifically directed at patients with decreased kidney function, and reviewed an extensive number of relevant articles. The potential weaknesses are inherent to all retrospective studies: the conclusions depend on the validity of the selected studies, there may be selection bias for the articles ultimately evaluated based on preexisting hypotheses, interpretation of the selected articles may be affected by preexisting hypotheses, and the methods used to analyze the articles will affect the conclusions. How does this study compare with prior studies?Lu et al8Lu W.R. Defilippi J. Braun A. Unleash metformin: reconsideration of the contraindication in patients with renal impairment.Ann Pharmacother. 2013; 47: 1488-1497Crossref PubMed Scopus (30) Google Scholar performed a similar online database search covering the period from 1950 to August 2013, but limited their review to 6 articles, all of which were included in the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar article. In this smaller article set, Lu et al8Lu W.R. Defilippi J. Braun A. Unleash metformin: reconsideration of the contraindication in patients with renal impairment.Ann Pharmacother. 2013; 47: 1488-1497Crossref PubMed Scopus (30) Google Scholar reached the same conclusions as Inzucchi et al.7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar Most of the other previous studies are included in the analysis conducted by Inzucchi et al.7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar Salpeter et al9Salpeter S.R. Greyber E. Pasternak G.A. Salpeter E.E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.Cochrane Database Syst Rev. 2010; 14: CD002967Google Scholar evaluated 347 comparative trials and cohort studies in a systematic review and noted that no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use were observed. There was no difference in lactate levels in individuals treated with metformin versus nonmetformin therapies. This analysis did not specifically focus on patients with CKD, but the authors included studies evaluating people with CKD in their analysis.Other relevant studies were based on analyses of patient databases. Ekstrom et al2Ekstrom N. Schioler L. Svensson A.M. et al.Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register.BMJ Open. 2012; 2Crossref Scopus (175) Google Scholar evaluated 51,675 patients from Sweden’s National Registries. No increased risk of metformin-associated lactic acidosis was seen in any group, including patients with CKD. Rather, the authors reported that metformin use was associated with reduced risk of cardiovascular disease, acidosis/serious infection, and all-cause mortality compared with insulin and reduced risk of all-cause mortality compared with other oral hypoglycemic agents.Bodmer et al10Bodmer M. Meier C. Krahenbuhl S. Jick S.S. Meier C.R. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis.Diabetes Care. 2008; 31: 2086-2091Crossref PubMed Scopus (347) Google Scholar analyzed the UK-based General Practice Research Database. In the study population of 50,048 patients with T2DM, 6 cases of lactic acidosis were identified. No difference between metformin and other oral hypoglycemic agents was observed. The authors concluded that lactic acidosis was very rare and was associated with concurrent comorbid conditions.In contrast, a recent report by Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar showed a different result. They evaluated the same database that Bodmer et al10Bodmer M. Meier C. Krahenbuhl S. Jick S.S. Meier C.R. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis.Diabetes Care. 2008; 31: 2086-2091Crossref PubMed Scopus (347) Google Scholar analyzed except that Bodmer et al evaluated patient data from 1994 to 2005, whereas Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar studied the period from 2004 to 2012. They found an increased risk for lactic acidosis in patients using metformin with eGFRs < 60 mL/min. This risk was further increased in patients with decreased eGFRs taking >730 g per year of metformin (>2 g/d). Thus, they concluded that metformin risk for lactic acidosis was both dose and GFR dependent. Published in the same issue of Diabetes Care, Richy et al12Richy F.F. Sabido-Espin M. Guedes S. Corvino F.A. Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study.Diabetes Care. 2014; 37: 2291-2295Crossref PubMed Scopus (74) Google Scholar analyzed the same database from 2007 to 2012. They found very low lactic acidosis event rates that increased with decreased kidney function; however, reflecting the very low rates, they concluded that these differences were not clinically significant.12Richy F.F. Sabido-Espin M. Guedes S. Corvino F.A. Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study.Diabetes Care. 2014; 37: 2291-2295Crossref PubMed Scopus (74) Google Scholar The different conclusions from these 3 studies using the same database are likely due to variable methods used to analyze the data and varying ascertainment periods.Taken together, these findings suggest that it is reasonable to liberalize the dosing recommendations. Other countries have already changed their recommendations. For example, Canadian and Australian guidelines recommend using metformin with caution and reducing the metformin dose when eGFR is 30 to 60 mL/min/1.73 m2. Both guidelines recommend discontinuing metformin therapy when eGFR is <30 mL/min/1.73 m2.13Booth G. Cheng A.Y. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Methods.Can J Diabetes. 2013; 37: S61-S68Google Scholar, 14The Royal Australian College of General Practitioners. General practice management of type 2 diabetes. 2014-2015. http://www.racgp.org.au/your-practice/guidelines/diabetes/. Accessed February 22, 2015.Google Scholar Lu et al8Lu W.R. Defilippi J. Braun A. Unleash metformin: reconsideration of the contraindication in patients with renal impairment.Ann Pharmacother. 2013; 47: 1488-1497Crossref PubMed Scopus (30) Google Scholar performed a similar online database search covering the period from 1950 to August 2013, but limited their review to 6 articles, all of which were included in the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar article. In this smaller article set, Lu et al8Lu W.R. Defilippi J. Braun A. Unleash metformin: reconsideration of the contraindication in patients with renal impairment.Ann Pharmacother. 2013; 47: 1488-1497Crossref PubMed Scopus (30) Google Scholar reached the same conclusions as Inzucchi et al.7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar Most of the other previous studies are included in the analysis conducted by Inzucchi et al.7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar Salpeter et al9Salpeter S.R. Greyber E. Pasternak G.A. Salpeter E.E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.Cochrane Database Syst Rev. 2010; 14: CD002967Google Scholar evaluated 347 comparative trials and cohort studies in a systematic review and noted that no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use were observed. There was no difference in lactate levels in individuals treated with metformin versus nonmetformin therapies. This analysis did not specifically focus on patients with CKD, but the authors included studies evaluating people with CKD in their analysis. Other relevant studies were based on analyses of patient databases. Ekstrom et al2Ekstrom N. Schioler L. Svensson A.M. et al.Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register.BMJ Open. 2012; 2Crossref Scopus (175) Google Scholar evaluated 51,675 patients from Sweden’s National Registries. No increased risk of metformin-associated lactic acidosis was seen in any group, including patients with CKD. Rather, the authors reported that metformin use was associated with reduced risk of cardiovascular disease, acidosis/serious infection, and all-cause mortality compared with insulin and reduced risk of all-cause mortality compared with other oral hypoglycemic agents. Bodmer et al10Bodmer M. Meier C. Krahenbuhl S. Jick S.S. Meier C.R. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis.Diabetes Care. 2008; 31: 2086-2091Crossref PubMed Scopus (347) Google Scholar analyzed the UK-based General Practice Research Database. In the study population of 50,048 patients with T2DM, 6 cases of lactic acidosis were identified. No difference between metformin and other oral hypoglycemic agents was observed. The authors concluded that lactic acidosis was very rare and was associated with concurrent comorbid conditions. In contrast, a recent report by Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar showed a different result. They evaluated the same database that Bodmer et al10Bodmer M. Meier C. Krahenbuhl S. Jick S.S. Meier C.R. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis.Diabetes Care. 2008; 31: 2086-2091Crossref PubMed Scopus (347) Google Scholar analyzed except that Bodmer et al evaluated patient data from 1994 to 2005, whereas Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar studied the period from 2004 to 2012. They found an increased risk for lactic acidosis in patients using metformin with eGFRs < 60 mL/min. This risk was further increased in patients with decreased eGFRs taking >730 g per year of metformin (>2 g/d). Thus, they concluded that metformin risk for lactic acidosis was both dose and GFR dependent. Published in the same issue of Diabetes Care, Richy et al12Richy F.F. Sabido-Espin M. Guedes S. Corvino F.A. Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study.Diabetes Care. 2014; 37: 2291-2295Crossref PubMed Scopus (74) Google Scholar analyzed the same database from 2007 to 2012. They found very low lactic acidosis event rates that increased with decreased kidney function; however, reflecting the very low rates, they concluded that these differences were not clinically significant.12Richy F.F. Sabido-Espin M. Guedes S. Corvino F.A. Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study.Diabetes Care. 2014; 37: 2291-2295Crossref PubMed Scopus (74) Google Scholar The different conclusions from these 3 studies using the same database are likely due to variable methods used to analyze the data and varying ascertainment periods. Taken together, these findings suggest that it is reasonable to liberalize the dosing recommendations. Other countries have already changed their recommendations. For example, Canadian and Australian guidelines recommend using metformin with caution and reducing the metformin dose when eGFR is 30 to 60 mL/min/1.73 m2. Both guidelines recommend discontinuing metformin therapy when eGFR is 90 mL/min, holding the drug 1 day before a procedure will lead to an ∼90% decrease in drug level.16Bristol Meyers Squibb. Glucophage [package insert]. 2015. http://packageinserts.bms.com/pi/pi_glucophage_xr.pdf. Accessed February 21, 2015.Google Scholar At lower GFRs, there is decreased clearance; thus, holding the drug therapy 2 or 3 days before a procedure might be indicated in people with lower GFRs.4.Is there a risk using metformin in combination with medications that lower GFR (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, etc)? There are very few data about this question, but it appears prudent to follow up individual patients’ eGFRs and decrease metformin dose or hold the dose based on the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar recommendations for dosing based on eGFR.5.How often do eGFRs need to be monitored in individuals treated with metformin? eGFR should be assessed every 3 to 6 months depending on baseline eGFR, stability of eGFR, other medications, and chronic comorbid conditions and more frequently during acute medical events.6.Is there an upper age limit for using metformin? This is unclear, but data suggest that adjusting the dose for eGFR is also the best approach.Current data clearly show that the risk for metformin-associated lactic acidosis is low. Even in the Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar study, in which an increased risk for metformin-associated lactic acidosis with decreased GFR was reported, event rates were very low (21 events/126,881 person-years of metformin use in patients with GFRs < 60 mL/min and 29/547,731 for patients with GFRs > 60 mL/min). Hence, even in individuals with stage 3 CKD, the absolute risk of metformin-associated lactic acidosis is low.17Lalau J.D. Arnouts P. Sharif A. De Broe M.E. Metformin and other antidiabetic agents in renal failure patients.Kidney Int. 2015; 87: 308-322Crossref PubMed Scopus (89) Google ScholarIn conclusion, the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar study provides further support for changing the metformin dosing recommendations in the United States, as has already been done in Canada13Booth G. Cheng A.Y. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Methods.Can J Diabetes. 2013; 37: S61-S68Google Scholar and Australia.14The Royal Australian College of General Practitioners. General practice management of type 2 diabetes. 2014-2015. http://www.racgp.org.au/your-practice/guidelines/diabetes/. Accessed February 22, 2015.Google Scholar Considering the efficacy of metformin, the low risk of lactic acidosis, and the increasing number of people with T2DM and CKD, the recommendations by Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar are reasonable. Prospective studies would be ideal but, as Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar note, it is very unlikely that definitive prospective studies will ever be performed because event rates are so low that the sample size for any study would have to be very large, with participants followed up over many years. There are a number of other clinical questions.1.Should metformin drug levels be used to assess risk? While there are not enough studies evaluating whether there is an association between metformin levels and lactic acidosis, the studies that have been done do not show clear correlation between drug level and risk of lactic acidosis. Accordingly, routine assessment of metformin drug levels cannot be recommended.2.Should metformin treatment be held in a patient with AKI? Given the data showing that cases of metformin-associated lactic acidosis appear to be linked to concurrent comorbid events, including AKI, and dependence on GFR for metformin clearance, it appears appropriate to discontinue metformin treatment until AKI resolves.3.Should metformin therapy be stopped prior to a radiocontrast dye study? In this setting, the risk of metformin-associated lactic acidosis appears to be related to the occurrence of AKI.15Goergen S.K. Rumbold G. Compton G. Harris C. Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin.Radiology. 2010; 254: 261-269Crossref PubMed Scopus (96) Google Scholar Thus, if there is concern for decreased GFR, it appears appropriate to hold metformin treatment in this setting. The half-life of metformin in patients without CKD is 6.2 hours.16Bristol Meyers Squibb. Glucophage [package insert]. 2015. http://packageinserts.bms.com/pi/pi_glucophage_xr.pdf. Accessed February 21, 2015.Google Scholar Hence, in patients with GFRs > 90 mL/min, holding the drug 1 day before a procedure will lead to an ∼90% decrease in drug level.16Bristol Meyers Squibb. Glucophage [package insert]. 2015. http://packageinserts.bms.com/pi/pi_glucophage_xr.pdf. Accessed February 21, 2015.Google Scholar At lower GFRs, there is decreased clearance; thus, holding the drug therapy 2 or 3 days before a procedure might be indicated in people with lower GFRs.4.Is there a risk using metformin in combination with medications that lower GFR (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, etc)? There are very few data about this question, but it appears prudent to follow up individual patients’ eGFRs and decrease metformin dose or hold the dose based on the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar recommendations for dosing based on eGFR.5.How often do eGFRs need to be monitored in individuals treated with metformin? eGFR should be assessed every 3 to 6 months depending on baseline eGFR, stability of eGFR, other medications, and chronic comorbid conditions and more frequently during acute medical events.6.Is there an upper age limit for using metformin? This is unclear, but data suggest that adjusting the dose for eGFR is also the best approach. Current data clearly show that the risk for metformin-associated lactic acidosis is low. Even in the Eppenga et al11Eppenga W.L. Lalmohamed A. Geerts A.F. et al.Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study.Diabetes Care. 2014; 37: 2218-2224Crossref PubMed Scopus (116) Google Scholar study, in which an increased risk for metformin-associated lactic acidosis with decreased GFR was reported, event rates were very low (21 events/126,881 person-years of metformin use in patients with GFRs < 60 mL/min and 29/547,731 for patients with GFRs > 60 mL/min). Hence, even in individuals with stage 3 CKD, the absolute risk of metformin-associated lactic acidosis is low.17Lalau J.D. Arnouts P. Sharif A. De Broe M.E. Metformin and other antidiabetic agents in renal failure patients.Kidney Int. 2015; 87: 308-322Crossref PubMed Scopus (89) Google Scholar In conclusion, the Inzucchi et al7Inzucchi S.E. Lipska K.J. Mayo H. Bailey C.J. McGuire D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review.JAMA. 2014; 312: 2668-2675Crossref PubMed Scopus (405) Google Scholar study provides further support for changing the metformin dosing recommendations in the United States, as has already been done in Canada13Booth G. Cheng A.Y. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Methods.Can J Diabetes. 2013; 37: S61-S68Google Scholar and Australia.14The Royal Australian College of General Practitioners. General practice management of type 2 diabetes. 2014-2015. http://www.racgp.org.au/your-practice/guidelines/diabetes/. Accessed February 22, 2015.Google Scholar Support: None. Financial Disclosure: Dr Stanton serves on the Renal Advisory Board for Boehringher-Ingelheim and receives research support from Beohringer-Ingelheim. Restricting Metformin in CKD: Continued Caution WarrantedAmerican Journal of Kidney DiseasesVol. 66Issue 6PreviewGiven the low observed incidence of metformin-associated lactic acidosis (MALA) in a systematic review of diabetic patients with and without CKD,1 a commentary by Stanton2 recommends liberalizing metformin use in CKD, namely, continuation at a reduced dose over an eGFR range of 30-60 mL/min/1.73 m2. The FDA black box warning and NKF-KDOQI recommendations advise against metformin with Scr levels ≥ 1.4 mg/dL and ≥1.5 mg/dL in men and women, respectively (Table 1).3,4 We are concerned about relaxing restrictions for 3 primary reasons. Full-Text PDF
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