The 2023 Standards of Care in Diabetes guidelines from the American Diabetes Association (ADA) recommend metformin (brand names Fortamet, Glumetza, discontinued brand names Glucophage, Riomet) as first line treatment for adults and children ten years and older with type 2 diabetes.1 Metformin is a biguanide drug that works to reduce both basal and postprandial plasma glucose through reducing glucose production by the liver, increasing sensitivity to insulin, and decreasing intestinal absorption of glucose.2,3 Metformin is not metabolized by the liver and is excreted mostly unchanged in urine. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours of ingestion.
Although exceedingly rare, metformin is thought to increase the risk of lactic acidosis among those with severe renal impairment.1 Lactic acidosis is a serious adverse event that can reduce cardiac and vascular contractility and may increase mortality.4 Metformin decreases liver uptake of lactate, increasing lactate levels in the blood.5 In patients with decreased renal function, the plasma half-life of metformin is prolonged and renal clearance is decreased. This can lead to a buildup of metformin which can block pyruvate carboxylase in gluconeogenesis, increasing the risk for lactic acidosis.
The exact increase in incidence of lactic acidosis among those taking metformin is difficult to estimate, mostly due to its rarity and rates being approximated by case report. There is limited information on the incidence of lactic acidosis in patients with type 2 diabetes not taking metformin to use as a baseline for comparison. The population taking metformin also tend to have confounding comorbidities such as obesity, elevated hemoglobin A1c, and heart failure.4,6
One systematic review and meta-analysis estimated the incidence of lactic acidosis to be 8.1 cases per 100,000 person-years among those taking metformin and 9.9 cases per 100,000 person-years among a comparable population not taking metformin.7 Another study that accounted for 41,436 person-years of data estimated the incidence of lactic acidosis among those with type 2 diabetes to be 9.7 cases per 100,000 patient-years, which is similar to the incidence reported among those taking metformin.8
Over the first year of use of metformin in the United States, during which approximately one million patients started treatment, the Food and Drug Administration (FDA) received 47 confirmed reports of lactic acidosis, 20 of which were fatal.9 Of those 47 cases, 43 had renal failure or other risk factors for lactic acidosis, primarily congestive heart failure. Only four patients did not have other risk factors for lactic acidosis when starting metformin, and all four recovered. Even counting cases that may not have been precipitated by metformin, the estimated incidence is five cases per 100,000 people.
A 2008 case-control analysis of 50,048 patients with type 2 diabetes being treated with at least one prescription found five incidents of lactic acidosis among those taking metformin, only one of whom used metformin alone as their treatment.10 The crude incidence rate was 3.3 cases per 100,000 person-years.
A 1999 study (n=11,797) seeking to quantify the incidence of lactic acidosis in metformin users found only two confirmed cases of elevated blood lactate levels over 22,296 person-years, making the incidence rate about 0.02%, or 9.0 cases per 100,000 person-years.11
A 2014 population-level cohort study (n=223,968) sought to determine whether treatment with metformin in patients with renal impairment is associated with higher risk of elevated lactate concentrations.6 The incidence of elevated lactate concentrations (including lactic acidosis) among those taking metformin was 7.4 per 100,000 person-years vs. 2.2 in nonusers. However, at a population level, this increased risk was not statistically significant. The only statistically significant increase in risk occurred among those with lower eGFR, with an incidence of 23.5 per 100,000 person-years in participants with an eGFR <45 mL/min/1.73 m2 (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] [1.34-33.8]) vs 6.7 for those with an eGFR ≥45 mL/min/1.73 m2 (adjusted HR 3.16, 95% CI [0.75-13.3]).
A 2018 retrospective community-based cohort study (n=75,413) examined the risk of lactic acidosis in metformin users with a range of kidney functions (assessed with eGFR).12 Metformin use was not associated with an increased risk of acidosis among those with normal renal function (0.4% incidence, adjusted HR 0.87-1.07, 95% CI [0.75-1.41]) and even moderate renal impairment (1% incidence, adjusted HR 1.09, 95% CI [0.95-1.41]). However, among those with eGFR <30 mL/min/1.73 m2, metformin was associated with an increased risk of acidosis (4% incidence, adjusted HR 2.07, 95% CI [1.33-3.22]).
Because of this, metformin is contraindicated for individuals with severe renal impairment (estimated globular filtration rate [eGFR] <30 mL/min/1.73 m2), known hypersensitivity to metformin, and acute or chronic metabolic acidosis, including diabetic ketoacidosis.2,3 Manufacturers do not recommend the use of metformin in individuals with moderate renal impairment (eGFR 30-45 mL/min/1.73 m2).2,3 However, ADA clinical practice guidelines as well as the Food and Drug Administration (FDA) state that metformin is safe to use in people with reduced eGFR ≥30 mL/min/1.73 m2.1,13
There is no evidence that metformin affects kidney function, regardless of renal impairment. One retrospective cohort study compared adverse kidney events in those with decreased kidney function (eGFR <60 mL/min/ m2) with metformin to sulfonylurea use.14 There were 49 adverse kidney events among the 24,883 patients taking metformin (0.20%, 2.9 events per 1,000 person-years) and 56 among the 24,998 taking sulfonylureas (0.22%, 3.1 events per 1,000 person-years).
Another observational cohort study (n= 25,148) found that metformin use was not associated with acute kidney injury incidence, with 32.4 cases per 10,000 person-years in those taking metformin vs 44.9 cases per 10,000 person-years for those not taking it (adjusted HR 0.94, 95% CI [0.87-1.02], p=0.15).15
Dosage recommendations based on renal functioning vary worldwide. The Australian Medicines Handbook and the New Zealand Formulary recommend a maximum daily dose of 1,000 mg for creatinine clearance of 30-60 mL/min.16,17 The New Zealand Formulary further recommends a maximum daily dose of 500 mg for creatinine clearance of 15-30. The United States and Canada have no recommended dose and advise caution in prescribing metformin to those with eGFR <60 mL/min/1.73 m2.1,18
To monitor the continued efficacy of metformin use, manufacturers recommend monitoring renal function testing at least annually during treatment with metformin.2,3 For those with renal impairment or at risk of developing renal impairment, they recommend renal function be assessed more frequently.
References
- ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. Jan 1 2023;46(Suppl 1):S140-s157. doi:10.2337/dc23-S009
- Glucophage (metformin hydrochloride) tablets, for oral use & Glucophage XR (metformin hydrochloride) extended-release tablets, for oral use. [Package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018.
- Riomet (metformin hydrochloride) oral solution. [Package insert]. Cranbury, NJ: Sun Pharmaceutical Industries; 2018.
- Luft FC. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol. Feb 2001;12 Suppl 17:S15-9.
- Blough B, Moreland A, Mora A, Jr. Metformin-induced lactic acidosis with emphasis on the anion gap. Proc (Bayl Univ Med Cent). 2015:31-3. vol. 1.
- 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. Aug 2014;37(8):2218-24. doi:10.2337/dc13-3023
- Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. Apr 14 2010;2010(4):CD002967.
- Brown JB, Pedula K, Barzilay J, Herson MK, Latare P. Lactic acidosis rates in type 2 diabetes. Diabetes Care. Oct 1998;21(10):1659-63. doi:10.2337/diacare.21.10.1659
- Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. Jan 22 1998;338(4):265-6. doi:10.1056/nejm199801223380415
- Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care. Nov 2008;31(11):2086-91. doi:10.2337/dc08-1171
- Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care. Jun 1999;22(6):925-7. doi:10.2337/diacare.22.6.925
- Lazarus B, Wu A, Shin JI, et al. Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study. JAMA Intern Med. Jul 1 2018;178(7):903-910. doi:10.1001/jamainternmed.2018.0292
- FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. U.S. Food and Drug Administration; 2016.
- Hung AM, Hackstadt AJ, Griffin MR, Grijalva CG, Greevy RA, Jr., Roumie CL. Comparative effectiveness of metformin versus sulfonylureas on kidney function decline or death among patients with reduced kidney function: a retrospective cohort study. CMAJ Open. Jan-Feb 2023;11(1):E77-e89. doi:10.9778/cmajo.20210207
- Bell S, Farran B, McGurnaghan S, et al. Risk of acute kidney injury and survival in patients treated with Metformin: an observational cohort study. BMC Nephrol. May 19 2017;18(1):163. doi:10.1186/s12882-017-0579-5
- Australian Medicines Handbook 2016. Australian Medicines Handbook Pty Ltd; 2017.
- Metformin Hydrochloride. New Zealand Formulary. Accessed 21 June 2023, https://nzf.org.nz/nzf_3715
- Lipscombe L, Butalia S, Dasgupta K, et al. Pharmacologic Glycemic Management of Type 2 Diabetes in Adults: 2020 Update. Can J Diabetes. Oct 2020;44(7):575-591. doi:10.1016/j.jcjd.2020.08.001
