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. 2010 Apr 14;2010(4):CD002967.
doi: 10.1002/14651858.CD002967.pub4.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

Shelley R Salpeter  1 , Elizabeth Greyber, Gary A Pasternak, Edwin E Salpeter
Affiliations

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

Shelley R Salpeter et al. Cochrane Database Syst Rev. .

Abstract

Background: Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age.

Objectives: To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies.

Search strategy: A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators.

Selection criteria: Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy.

Data collection and analysis: The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data.

Main results: Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies.

Authors' conclusions: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

PubMed Disclaimer

Conflict of interest statement

None known.

Figures

1.1
1.1. Analysis
Comparison 1 Fatal/nonfatal lactic acidosis, Outcome 1 Lactic acidosis incidence per patient‐years (metformin minus non‐metformin).
2.1
2.1. Analysis
Comparison 2 Blood lactate levels, Outcome 1 Net treatment effect, lactate levels (mmol/L).
2.2
2.2. Analysis
Comparison 2 Blood lactate levels, Outcome 2 Mean treatment lactate levels (mmol/L).
2.3
2.3. Analysis
Comparison 2 Blood lactate levels, Outcome 3 Peak stimulated lactate levels (mmol/L).
See this image and copyright information in PMC

Update of

References

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Sahin 2007 {published data only}
    1. Sahin M, Tutuncu NB, Ertungrul D, Tanaci N, Guvener ND. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, flotae and vitamin B12 in patients with type 2 diabetes mellitus. Journal of Diabetes and its Complications 2007;21:118‐123. - PubMed
Sanchez‐Barba 1999 {published data only}
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Santos 1995 {published data only}
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Schernthaner 2004 {published data only}
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Schiel 2008 {published data only}
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Schneider 1990 {published data only}
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Schulte 1973 {published data only}
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Schwartz 2006 {published data only}
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Schweizer 2007 {published data only}
    1. Schweizer A, Couturier A, Foley JE, Dejager S. Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1 year in drug‐naive patients with Type 2 diabetes. Diabetic Medicine 2007;24(9):955‐61. - PubMed
Schweizer 2009 {published data only}
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Scott 2008 {published data only}
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Sharma 2006 {published data only}
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Shimpi 2009 {published data only}
    1. Shimpi RD, Patil PH, Kuchake VG, Ingle PV, Surana SJ, Dighore PN. Comparison of effect of metformin in combination with glimepiride and glibenclamide on glycaemic control in patient with type 2 Diabetes Mellitus. International Journal of PharmTech Research 2009, (1):50‐61.
Sieradzki 1999 {published data only}
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Stades 2000 {published data only}
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Stalhammar 1991 {published data only}
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Standl 2001 {published data only}
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Sterne 1963 {published data only}
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Stewart 2006 {published data only}
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Stocker 2007 {published data only}
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Stratmann 1965 {published data only}
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Strowig 2002 {published data only}
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Stumvoll 1995 {published data only}
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Sundaresan 1997 {published data only}
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Swislocki 1999 {published data only}
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Szanto 1964 {published data only}
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Taylor 1982 {published data only}
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Teranishi 2007 {published data only}
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Tessari 1994 {published data only}
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Tessier 1999 {published data only}
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Testa 1996 {published data only}
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Teupe 1991 {published data only}
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Tikkainen 2004 {published data only}
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Topiak 2007 {published data only}
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Tosi 2003 {published data only}
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Triplitt 2006 {published data only}
    1. Triplitt C, Glass L, Miyazaki Y, Wajcberg W, Gastaldelli Am, Filippis E, Cersosimo E, DeFronzo RA. Comparison of glargine insulin versus rosiglitazone addition in poorly controlled trype 2 diabetic patients on metformin plus sulfonylurea. Diabetes Care 2006;29:2371‐2377. - PubMed
Trischitta 1992 {published data only}
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Trischitta 1998 {published data only}
    1. Trischitta V, Italia S, Raimondo M, Guardabasso V, Licciardello C, Runello F, et al. Efficacy of combined treatments in NIDDM patients with secondary failure to sulphonylureas. Is it predictable?. Journal of Endocrinological Investigation 1998;21(11):744‐7. - PubMed
Turkmen 2007 {published data only}
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Uehara 2001 {published data only}
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UKPDS‐34 1998 {published data only}
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    1. Turner RC, Cull CA, Frighi V, Holman RR, and the UK Prospective Diabetes Study Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. Journal of the American Medical Association 1999;281(21):2005‐12. - PubMed
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Umpierrez 2006 {published data only}
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Vahatalo 2007 {published data only}
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van der Meer 2009 {published data only}
    1. Meer RW, Rijzewijk LJ, Jong HW, Lamb HJ, Lubberink M, Romijn JA, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high‐energy phosphate metabolism in patients with well‐controlled type 2 diabetes mellitus.[see comment]. Circulation 2009;119(15):2069‐77. - PubMed
Van Gaal 2001 {published data only}
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Vannasaeng 1995 {published data only}
    1. Vannasaeng S, Ploybutr S, Nitiyanant W, Peerapatdit T, Vichayanrat A. Effects of alpha‐glucosidase inhibitor (acarbose) combined with sulfonylurea or sulfonylurea and metformin in treatment of non‐insulin‐dependent diabetes mellitus. Journal of the Medical Association of Thailand 1995;78(11):578‐85. - PubMed
Velojic‐Golubovic 2009 {published data only}
    1. Velojic‐Golubovic M, Mikic D, Pesic M, Dimic D, Radenkovic S, Antic S. Biphastic insulin aspart 30: Better glycemic control than with premixed human insulin 30 in obese patients with Type 2 diabetes. Journal of Endocrinological Investigation 2009;32(1):23‐7. - PubMed
Velussi 1992 {published data only}
    1. Velussi M, Cernigoi AM, Viezzoli L, Caffau C. [Median‐term (4 months) treatment with glibenclamide + metformin substituting for glibenclamide + fenformin lowers the lacticemia levels in type‐2 diabetics (NIDDM)]. La Clinical Terapeutica 1992;141(12):483‐92. - PubMed
Vigneri 1991 {published data only}
    1. Vigneri R, Trischitta V, Italia S, Mazzarino S, Rabuazzo MA, Squatrito S. Treatment of NIDDM patients with secondary failure to glyburide: comparison of the addition of either metformin or bed‐time NPH insulin to glyburide. Diabete & Metabolisme 1991;17(1 Pt 2):232‐4. - PubMed
Viljanen 2005 {published data only}
    1. Viljanen APM, Virtanen KA, Jarvisalo MJ, Hallsten K, Parkkola R, Ronnemaa T, Lonnqvist F, Iozzo P, Ferrannini E, Nuutila P. Rosiglitazone treatment increases subcutaneous adipose tissue glucose uptake in parallel with perfusion in patients with type 2 diabetes: a double‐blind, randomized study with metformin. Journal of Clinical Endocrinology and Metabolism 2005;90:6523‐6528. - PubMed
Vukovic 2007 {published data only}
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Weissman 2005 {published data only}
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Willey 1992 {published data only}
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Willey 1994 {published data only}
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Willms 1999 {published data only}
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Wilson 1989 {published data only}
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Wolever 1995 {published data only}
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Wolever 2000 {published data only}
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Wu 1990 {published data only}
    1. Wu MS, Johnston P, Sheu WH, Hollenbeck CB, Jeng CY, Goldfine ID, et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13(1):1‐8. - PubMed
Wulffele 2000 {published data only}
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Wulffele 2002 {published data only}
    1. Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Burg BB, Fonker AJM, Stehouwer CDA. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002;25:2133‐40. - PubMed
Wulffele 2003 {published data only}
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Wulffele 2005 {published data only}
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Yale 2001 {published data only}
    1. Yale JF, Valiquett TR, Ghazzi MN, Owens‐Grillo JK, Whitcomb RW, Foyt HL. The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin: a multicenter, randomized, double‐blind, placebo‐controlled trrial. Annals of Internal Medicine 2001;134:737‐745. - PubMed
Yamanouchi 2005 {published data only}
    1. Yamanouchi T, Sakai T, Igarashi K, Ichiyanagi K, Watanabe H, Kawasaki T. Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed type 2 diabetes. Diabetic Medicine 2005;22:980‐5. - PubMed
Yener 2008 {published data only}
    1. Yener S, Comlekci A, Akinci B, Akan P, Demir T, Bayraktar F, et al. Serum transforming growth factor‐beta 1 levels in normoalbuminuric and normotensive patients with type 2 diabetes. Effect of metformin and rosiglitazone. Hormones 2008;7(1):70‐6. - PubMed
    1. Yener S, Comlekci A, Akinci B, Demir T, Yuksel F, Ozcan MA, et al. Soluble CD40 ligand, plasminogen activator inhibitor‐1 and thrombin‐activatable fibrinolysis inhibitor‐1‐antigen in normotensive type 2 diabetic subjects without diabetic complications. Effects of metformin and rosiglitazone. Medical Principles & Practice 2009;18(4):266‐71. - PubMed
Yki‐Jarvinen 1999 {published data only}
    1. Yki‐Jarvinen H, Ryysy L, Nikkila K, Tulokas T, Vanamo R, Heikkila M. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial [see comments]. Annals of Internal Medicine 1999;130(5):389‐96. - PubMed
Yu 1999 {published data only}
    1. Yu JG, Kruszynska YT, Mulford MI, Olefsky JM. A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin‐treated type 2 diabetic patients. Diabetes 1999;48(12):2414‐21. - PubMed
Zinman 2009 {published data only}
    1. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of the human glucagon‐like peptide‐1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD‐4 Met+TZD). Diabetes Care 2009;32(7):1224‐30. - PMC - PubMed

References to studies excluded from this review

Aguilar 1992b {published data only}
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Bruneder 1978 {published data only}
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Clauson 1996 {published data only}
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Debry 1966a {published data only}
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Debry 1966b {published data only}
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Derosa 2009 {published data only}
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English 2007 {published data only}
    1. English PJ, Ashcroft A, Patterson M, Dovey TM, Halford JC, Harrison J. Metformin prolongs the posptrandial fall in plasma ghrelin concentrations in type 2 diabetes. Diabetes Metabolism Research and Reviews 2007;23:299‐303. - PubMed
Eurich 2005a {published data only}
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Eurich 2005b {published data only}
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Evans 2006 {published data only}
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Fery 1997 {published data only}
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Galuska 1994 {published data only}
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Gibson 1995 {published data only}
    1. Gibson JM, Westwood M, Crosby SR, Gordon C, Holly JMP, Fraser W, Anderson C, White A, Young RJ. Choice of treatment affects plasma levels of insulin‐like growth factor‐binding protein‐1 in noninsulin‐dependent Diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1995;80:1369‐75. - PubMed
Gin 1982 {published data only}
    1. Gin H, Slama G, Weissbrodt P, Poynard T, Vexiau P, Klein JC, Tchobroutsky G. Metformin reduces post‐prandial insulin needs in Type 1 (Insulin‐dependent) diabetic patients: Assessment by the artificial pancreas. Diabetologia 1982;23:34‐6. - PubMed
Gin 1985 {published data only}
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Gin 1989 {published data only}
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Giugliano 1979 {published data only}
    1. Giugliano D, Torella R, Improta L, Scognamiglio G. Effects of metformin on plasma glucose, insulin, FFA, glucagon, growth hormone and cortisol responses to oral glucose in subjects with chemical diabetes. Farmaco edizione Pratica 1979;34(1):32‐41. - PubMed
Gontier 2008 {published data only}
    1. Gontier E, Fourme E, Wartski M, Blondet C, Bonardel G, Stanc E, et al. High and typical 18F‐FDG bowel uptake in patients treated with metformin. European Journal of Nuclear Medicine & Molecular Imaging 2008;35(1):95‐9. - PubMed
Guthrie 1997 {published data only}
    1. Guthrie R. Treatment of non‐insulin‐dependent diabetes mellitus with metformin. Journal of the American Board of Family Practice 1997;10(3):213‐21. - PubMed
Harris 2008 {published data only}
    1. Harris S, Yale J‐F, Dempsey E, Gerstein H. Can family physicians help patients initiate basal insulin therapy successfully?: Randomized trial of patient‐titrated insulin glargine compared with standard oral therapy: Lessons for family practice from the Canadian INSIGHT trial. Canadian Family Physician 2008;54(4):550‐8. - PMC - PubMed
He 2009 {published data only}
    1. He Y‐L, Sabo R, Picard F, Wang Y, Herron J, Ligueros‐Saylan M, et al. Study of the pharmacokinetic interaction of vildagliptin and metformin in patients with type 2 diabetes. Current Medical Research and Opinion 2009;25(5):1265‐72. - PubMed
Herman 2006 {published data only}
    1. Herman GA, Bergman A, Yi B, Kipnes M. Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase‐4 inhibitor sitagliptin when co‐administered in patients with type 2 diabetes. Clinical Medical Research and Opinion 2006;22:1939‐1947. - PubMed
Hermansen 2007 {published data only}
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Hirsch 2009 {published data only}
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    1. Home PD, Pocock SJ, Beck‐Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open‐label trial. The Lancet 2009;373(9681):2125‐35. - PubMed
Hong 2008 {published data only}
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Ismail 1978 {published data only}
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Jansson 1996 {published data only}
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Johansen 1999 {published data only}
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Kamber 2008 {published data only}
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Kim 2008 {published data only}
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Komajda 2008 {published data only}
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Lalau 1994 {published data only}
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Lalau 1995 {published data only}
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    1. Lapina IuV, Narusov OI, Mareev VI, Bolotina MG, Shestakova MV, Masenko VP, et al. [Efficacy and safety of the use of metformin in patients with chronic heart failure and type 2 diabetes mellitus. results of the study "rational effective mulicomponent therapy in the battle against diabetes mellitus in patients with chronic heart failure"]. [Russian]. Kardiologiia 2008;48(3):58‐68. - PubMed
Leslie 1987 {published data only}
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Lim 1970 {published data only}
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    1. Lin KD, Chang YH, Wang CL, Yang YH, Hsiao PJ, Li TH, et al. Thiazolidinedione addition reduces the serum retinol‐binding protein 4 in type 2 diabetic patients treated with metformin and sulfonylurea. Translational Research: The Journal Of Laboratory & Clinical Medicine 2008;151(6):309‐14. - PubMed
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Masoudi 2005 {published data only (unpublished sought but not used)}
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Messens 1965 {published data only}
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Messens 1966 {published data only}
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    1. Monami M, Luzzi C, Lamanna C, Chiasserini V, Addante F, Desideri CM, Masotti G, Marchionni N, Mannucci E. Three‐year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes and Metabolism Research and Reviews 2006;22:477‐482. - PubMed
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Muntoni 1965 {published data only}
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Nauck 1993 {published data only}
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Orlikowska 1966 {published data only}
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Panahloo 1995 {published data only}
    1. Panahloo A, Mohamed‐Ali V, Lane A, Green F, Humphries SE, Yudkin JS. Determinants of plasminogin activatory inhibitor 1 activiry in treated NIDDM and its relation to a polymorphosm in the Plasminogen Activator Inhibitor 1 gene. Diabetes 1995;44(1):37‐42. - PubMed
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Perriello 1994 {published data only}
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Pilger 1978 {published data only}
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Prager 1983 {published data only}
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Rambert 1961 {published data only}
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Rigas 1968 {published data only}
    1. Rigas AN, Bittles AH, Hadden DR, Montgomery DA. Circadian variation of glucose, insulin, and free fatty acids during long‐term use of oral hypoglycaemic agents in diabetes mellitus. British Medical Journal 1968;3(622):25‐8. - PMC - PubMed
Rizkalla 1986 {published data only}
    1. Rizkalla SW, Elgrably F, Tchobroutsky G, Slama G. Effects of metformin treatment on erythrocyte insulin binding in normal weight subjects, in obese non diabetic subjects, in type 1 and type 2 diabetic patients. Diabete & Metabolisme 1986;12(4):219‐24. - PubMed
Runge 2008 {published data only}
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Sambol 1996 {published data only}
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Scarpello 1998 {published data only}
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Schaffalitzky 1979 {published data only}
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Selby 1999 {published data only}
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Slama 1984 {published data only}
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Sugawara 1962 {published data only}
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Sum 1992 {published data only}
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Teitelbaum 1963 {published data only}
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Tomioka 2007 {published data only}
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Trischitta 1983 {published data only}
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