Metformin in advanced chronic kidney disease: are current guidelines overly restrictive?

Nicholas I Cole, Pauline A Swift, Rebecca J Suckling, Peter A Andrews


Type 2 diabetes mellitus and chronic kidney disease (CKD) frequently co-exist and the increasing burden of both conditions is a global concern. Metformin is established as the first-line treatment for type 2 diabetes because it is associated with improved cardiovascular outcomes and a reduced risk of hypoglycaemia compared with other treatment options. Patients with CKD may benefit in particular because they are at high risk of both cardiovascular disease and hypoglycaemic episodes. However, the use of metformin is restricted in this population due to the concerns over lactic acidosis. Recent reviews have evaluated this risk and concluded that current guidelines for prescribing metformin in CKD may be too restrictive. This narrative review considers this evidence further, but also examines the strength of evidence that favours the use of metformin in CKD patients.


type 2 diabetes mellitus, chronic kidney disease, metformin, biguanides, lactic acidosis, lactate, cardiovascular disease, hypoglycaemia

Full Text:



New JP, Middleton RJ, Klebe B, et al. Assessing the prevalence, monitoring and management of chronic kidney disease in patients with diabetes compared to those without diabetes in general practice. Diabet Med 2007;24:364-9.

Gilg J, Pruthi R, Fogarty D. UK Renal Registry 17th Annual Report: Chapter 1, UK Renal Replacement Therapy Incidence in 2013: National and Centre-specific Analyses. Bristol: UK Renal Registry 2014.

Ritz, E, Wolf G. Pathogenesis, clinical manifestations, and natural history of diabetic nephropathy. In: Floege J, Johnson RJ, Feehally J (eds) Comprehensive Clinical Nephrology, 4th Edition. St Louis: Saunders Elsevier, 2014: 359–78.

Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215-22.

Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalisation. N Engl J Med 2004; 351:1296-305.

International Diabetes Federation. Diabetes Atlas 2014, Sixth edition. Available from: 0.pdf (accessed 29 Oct 2015).

National Institute for Health and Care Excellence. The management of type 2 diabetes [CG87]. London: National Institute for Health and Care Excellence, 2009.

American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2014;37(Suppl 1):S14-80.

British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National Formulary 69: March 2015–September 2015. London: BMJ Publishing Group, 2015.

Hung SC, Chang YK, Liu JS, et al. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol 2015;3:605-14.

Inzucchi SE, Lipska KJ, Mayo H, et al. Metformin in patients with type 2 diabetes and kidney disease: a systemic review. JAMA 2014;312:2668-75.

Lalau JD, Arnouts P, Sharif A, et al. Metformin and other antidiabetic agents in renal failure patients. Kidney Int 2014;87:308-22.

Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.

Holman RR, Paul SK, Bethel MA, et al.10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.

The ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.

Perkovic V, Heerspink HL, Chalmers J, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int 2013;83:517-23.

Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129-39.

Shurraw S, Hemmelgarn B, Lin M, et al. Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population-based cohort study. Arch Intern Med 2011;171:1920-7.

Oomichi T, Emoto M, Tabata T, et al. Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study. Diabetes Care 2006;29:1496-500.

Drechsler C, Krane V, Ritz E, et al. Glycemic control and cardiovascular events in diabetic hemodialysis patients. Circulation 2009;120:2421-8.

Food and Drug Administration. Glucophage (metformin hydrochloride) final printed labeling. Food and Drug Administration 2001, US Department of Health and Human Services. Available from: (accessed 9 June 2015).

Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA consensus conference. Diabetes Care 2014;37:2864-83.

Dreyer G, Hull S, Aitken Z, et al. The effect of ethnicity on the prevalence of diabetes and associated chronic kidney disease. Q J Med 2009;102: 261-9.

Bailey RA, Wang Y, Zhu V, et al. Chronic kidney disease in US adults with type 2 diabetes: an updated national estimate of prevalence based on Kidney Disease: Improving Global Outcomes (KDIGO) staging. BMC Res Notes 2014;2:415. http://dx/doi/org/10.1186/1756-0500-7-415.

Rodriquez-Poncelas A, Garre-Olmo J, Franch-Nadal J, et al. Prevalence of chronic kidney disease in patients with type 2 diabetes in Spain: PERCEDIME2 study. BMC Nephrol 2013;14:46.

UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.

Saenz A, Fernandez-Esteban I, Mataix A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2005;3:CD002966. 14651858.cd002966.pub3

Cryer DR, Nicholas SP, Henry DH, et al. Comparative outcomes study of metformin intervention versus conventional approach: the COSMIC approach study. Diabetes Care 2005;28:539-43.

Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355:2427–43.

Nag S, Bilous R, Kelly W, et al. All-cause and cardiovascular mortality in diabetic subjects increases significantly with reduced estimated glomerular filtration rate (eGFR): 10 years’ data from the South Tees Diabetes Mortality study. Diabet Med 2007;24:10-17.

Rodriguez-Poncelas A, Coll-De Tuero G, Turrò-Garriga O, et al. Impact of chronic kidney disease on the prevalence of cardiovascular disease in patients with type 2 diabetes in Spain: PERCEDIME2 study. BMC Nephrol 2014;15:150. http://dx/

Cea Soriano L, Johansson S, Stefansson B, et al. Cardiovascular events and all-cause mortality in a cohort of 57,946 patients with type 2 diabetes: associations with renal function and cardiovascular risk factors. Cardiovasc Diabetol 2015;14:38.

Ekström N, Schiöler L, Svensson AM, 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;2:e001076.

Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013;36:1304-11.

Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 2010;170:1892–9.

Bodmer M, Meier C, Krähenbühl S, et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care 2008;31:2086-91.

The Action to Control Cardiovascular Risk in Type 2 Diabetes Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.

Khunti K, Davies M, Majeed A, et al. Hypoglycaemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type1 and type 2 diabetes: a cohort study. Diabetes Care 2015;38:316-22.

Moen MF, Zhan M, Van Doren H, et al. Frequency of hypoglycaemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1121-7.

MacGregor MS, Taal MW. Detection, Monitoring and Care of Patients with CKD. UK Renal Association, 2011. Available from: downloads (accessed 14 July 2015).

National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850-86.

Papademetriou V, Lovato L, Doumas M, et al. Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int 2015;87:649-59.

Hung AM, Roumie CL, Greevy RA, et al. Kidney function decline in metformin versus sulfonylurea initiators: assessment of time-dependent contribution of weight, blood pressure, and glycemic control. Pharmacoepidemiol Drug Saf 2013;22:623-31.

Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766-77.

Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomized clinical trials. Lancet 2007;370:1129-36.

Levin D, Bell S, Sund R, et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 2015;58:493-504.

Abdelmoneim AS, Eurich DT, Light PE, et al. Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. Diabetes Obes Metab 2015;17:523-32.

Gamble JM, Simpson SH, Eurich DT, et al. Insulin use and increased risk of mortality in type 2 diabetes: a cohort study. Diabetes Obes Metab 2010;12:47-53.

de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010;340:c2181.

Liu F, Lu JX, Tang JL, et al. Relationship of plasma creatinine and lactic acid in type 2 diabetic patients without renal dysfunction. Chin Med J (Engl) 2009;122:2547-53.

Mongraw-Chaffin ML, Matsushita K, Brancati FL, et al. Diabetes medication use and blood lactate level among participants with type 2 diabetes: the atherosclerosis risk in communities carotid MRI study. PLoS One 2012;7:e51237.

Davis TM, Jackson D, Davis WA, et al. The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: The Fremantle Diabetes Study. Br J Clin Pharmacol 2011;52:137-44.

Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2010;4:CD002967.

Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care 1997;22:925-7.

Brown JB, Pedula K, Barzilay J, et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998;21:1659-63.

Richy FF, Sabidó-Espin M, Guedes S, et al. 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;37:2291–5.

Eppenga WL, Lalmohamed A, Geerts AF, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 2014;37:2218-24.

Sambol NC, Chiang J, Lin ET, et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol 1995; 35:1094–102.

Frid A, Sterner GN, Löndahl M, et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 2010;33:1291-3.

Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994;24:49-57.

Kajbak F, Bennis Y, Hurtel-Lemaire AS, et al. Unexpectedly long half-life of metformin elimination in cases of metformin accumulation. Diabet Med 2016;33:105-10.

Stades AME, Heikens JT, Erkelens DW, et al. Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004;255:179-87.

Kamber N, Davis WA, Bruce DG, et al. Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study. Med J Aust 2008;188:446-9.

van Berlo-van de Laar IR, Vermeij CG, Doorenbos CJ. Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. J Clin Pharm Ther 2011;36:376-82.

Rachmani R, Slavachevski I, Levi Z, et al. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 2002;13:428.

Lim VC, Sum CF, Chan ES, et al. Lactate levels in Asian patients with type 2 diabetes mellitus on metformin and its association with dose of metformin and renal function. Int J Clin Pract 2007;61:1829-33.

Connolly V, Kesson CM. Metformin treatment in NIDDM patients with mild renal impairment. Postgrad Med J 1996;72:352-4.

Lalau JD, Vermersch A, Hary L, et al. Type 2 diabetes in the elderly: an assessment of metformin (metformin in the elderly). Int J Clin Pharmacol Ther Toxicol 1990;28:329-32.

Lin YC, Lin LY, Wang HF, et al. Fasting plasma lactate concentrations in ambulatory elderly patients with type 2 diabetes receiving metformin therapy: a retrospective cross-sectional study. J Chin Med Assoc 2010;73:617-22.

Duong JK, Roberts DM, Furlong TJ, et al. Metformin therapy in patients with chronic kidney disease. Diabetes Obes Metab 2012;14:963-5.

Al-Hwiesh AK, Abdul-Rahman IS, El-Deen MA, et al. Metformin in peritoneal dialysis: a pilot experience. Perit Dial Int 2014;34:368-75.

Lalau JD, Race JM. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999;20:377-84.

James MT, Hemmelgarn BR, Wiebe N, et al. Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study. Lancet 2010;376:2096-103.

Pantalone KM, Kattan MW, Yu C, et al. Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab 2012;14:803-09.

Wheeler S, Moore K, Forsberg CW, et al. Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy. Diabetologia 2013;56:1934-43.

Boussageon R, Gueyffier F, Cornu C. Metformin as firstline treatment for type 2 diabetes: are we sure? BMJ 2016;352:h6748.

Boussageon R, Supper I, Bejan-Angoulvant T, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012;9:e1001204.

Rao AD, Kuhadiya N, Reynolds K, et al. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality? Diabetes Care 2008;31:1672-8.

Chowdhury TA, Wright R, Yaqoob MM. Using metformin in the presence of renal disease: current guidelines are too restrictive, and many patients who could benefit are missing out. BMJ 2015;349:h1758.

Nye HJ, Herrington WG. Metformin: the safest hypoglycaemic agent in chronic kidney disease? Nephron Clin Pract 2011;118:380-3.

Anon. Metformin OK in CKD? Drugs Therapeutic Bulletin 2014;52:37.

Christiansen CF, Ehrenstein V, Heide-Jørgensen U, et al. Metformin initiation and renal impairment: a cohort study in Denmark and the UK. BMJ Open 2015;5:e008531.



  • There are currently no refbacks.

The Journal of the Association of British Clinical Diabetologists