By Lauren Strazzulla
Current FDA guidelines for the use of metformin stipulate that it not be prescribed to those with an elevated creatinine (at or above 1.5 mg/dL for men and 1.4 mg/dL for women). It is also contraindicated in patients with heart failure requiring pharmacologic treatment, and people over age 80, unless their creatinine demonstrates that renal function is not reduced. These guidelines are in place to prevent lactic acidosis, an understandably feared complication of metformin. However, metformin is, by consensus, the initial drug of choice in type 2 diabetes and may prevent or delay the disease in people with pre-diabetes. Metformin is used successfully with less restriction throughout Europe, where it is considered acceptable to prescribe as long as the patient’s glomerular filtration rate (GFR) exceeds 30 mL/minute .
Biguanides, such as metformin, act by improving insulin sensitivity and by suppressing inappropriate gluconeogenesis in the liver. They inhibit the mitochondrial respiratory chain, which shifts energy production from aerobic metabolism to anaerobic, generating lactic acid as a byproduct . Much of the concern for lactic acidosis (LA) arose from the legacy of metformin’s predecessor phenformin, which was removed from the market in 1978 due to high incidence of LA. But the pharmacokinetics of metformin differ markedly from phenformin, which has a longer half life and causes LA at a lower blood level relative to metformin [3,4].
The actual risk for lactic acidosis may be lower than widely believed. In fact, some studies have demonstrated that the vast majority of patients who get LA have serious underlying conditions, with the most common being infection, acute liver or kidney injury, and cardiovascular collapse [5,6,7]. A study by Lalau and colleagues found that survival in patients with LA correlates with the severity of the associated condition and not the degree of metformin accumulation. Metformin levels did not carry diagnostic or prognostic significance in patients with LA, and in some cases higher levels were associated with reduced mortality . These data call into question how significant a role metformin truly plays in potentiating lactic acidosis.
There has been speculation that patients with type 2 diabetes may already have a baseline risk for LA that is separate from the risk conferred by metformin use. Brown and colleagues (1998) showed that the rate of LA among patients with type 2 diabetes using metformin versus those not using metformin was indistinguishable, which implies that the pathogenesis of LA may be more closely related to the disease itself . Other studies have showed that the overall incidence of LA among metformin users is about 1 per 23,000-30,000 person-years compared to 1 per 18,000-21,000 person-years among diabetic patients on other agents [10,11]. Thus, metformin may not be as dangerous as previously thought.
Moreover, metformin has numerous health benefits that reduce the progression to diabetes as well as the disease burden. Metformin also provides the versatility of being able to be used with every other oral antidiabetic, in addition to insulin . The Diabetes Prevention Program study, which followed 30,000 people on metformin or placebo for an average of 3.2 years followed by a 7-8 year open label extension, showed that the drug produced significant weight loss and delayed or prevented diabetes. There were no cases of LA during the 18,000 patient-years of follow up . A retrospective analysis of over 19,000 patients enrolled in the REACH trial found that metformin was associated with a 24% reduction in all-cause mortality after only 2 years of use .
Yet, metformin is contraindicated in groups of patients for whom it is has a proven benefit. For example, metformin is contraindicated in heart failure because of a presumed increase in the LA risk. A meta-analysis performed in 2007 showed metformin to be the only antidiabetic drug not associated with harm to patients with both diabetes and heart failure; it also reduced mortality in these patients . Many cardiac catheterization lab protocols require withholding metformin 48 hours before and after the procedure. But there is concern that hyperglycemia from temporary cessation of metformin could be harmful during high-risk cardiac interventions [16,17]. Khurana and colleagues point out that metformin is not nephrotoxic and there is no known reaction with iodinated contrast . Similarly, among patients with moderate renal failure, metformin is associated with a reduction in mortality, though the drug is contraindicated in these patients according to current guidelines . Overall, evidence suggests that the benefits likely outweigh the risks for metformin in patients with heart failure and moderate renal failure–at least in those younger than 80 .
Metformin is a medication that helps mitigate the consequences of diabetes. Current FDA contraindications do not reflect the evidence suggesting that adverse events from metformin are uncommon, even among at-risk groups. The 2015 guidelines by the American Diabetes Association and the European Association for the Study of Diabetes maintain that the current cutoffs for renal safety are overly restrictive and recognize that many practitioners use metformin even when GFR falls to less than 60 mL/min . In fact, other studies have suggested that metformin remains within the therapeutic range and lactate levels are not significantly affected as long as estimated GFR is greater than 30 mL/minute . Therefore, it is time to re-evaluate metformin prescribing practices, given that this medication can safely improve the outlook for many patients who may not currently be eligible for the drug.
Commentary by Michael Tanner, MD Executive Editor, Clinical Correlations
Dimethyl biguanide (metformin) was first synthesized from Galega officinalis (French lilac) in the1920s. Jean Sterne, the French physician who developed it in the 1950s, coined its first trade name “Glucophage” (glucose eater). It was added to the British National Formulary in 1958. Metformin was not approved in the United States until 1994, largely due to guilt by association with the other truly dangerous biguanides phenformin and buformin. In 1998, the United Kingdom Prospective Diabetes Study (UKPDS 34) found that metformin monotherapy in overweight diabetics reduced all-cause mortality by 36% at 10.7 years compared to diet, and was associated with better patient outcomes compared with insulin supply-side drugs–glyburide, chlorpropamide, and insulin itself . The UKPDS was largely responsible for the American Diabetes Association’s eventual recommendation that metformin, barring contraindications, should be the first-line pharmacological agent in most cases of type 2 diabetes.
Citizen petitions were submitted in 2012 and 2013 to relax the FDA’s draconian metformin rules, which are based, inexplicably, on creatinine level rather than GFR. The FDA needs to relax the no-metformin cutoff to a GFR of <30 mL/minute, so that the nearly one million diabetic patients for whom metformin is unnecessarily contraindicated can benefit.
Lauren Strazzulla is a third year medical student at NYU Langone School of Medicine
Michael Tanner, MD is an Associate Professor of Medicine and Executive Editor, Clinical Correlations
- Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 1 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203. http://care.diabetesjournals.org/content/32/1/193.full
- Cho YM, Kieffer TJ. New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia. 2011:54(2):219-222. http://www.ncbi.nlm.nih.gov/pubmed/21116606
- Sirtori CR, Franceschini G, Galli-Kienle M, et al. Disposition of metformin (N,N-dimethylbiguanide) in man. Clin Pharmacol Ther. 1978:24(6):683-693. http://www.ncbi.nlm.nih.gov/pubmed/710026
- Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014:10(3):143-156. http://www.nature.com/nrendo/journal/v10/n3/full/nrendo.2013.256.html
- 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. http://jama.jamanetwork.com/article.aspx?articleid=2084896
- 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.1998:338:265-266. http://www.nejm.org/doi/full/10.1056/NEJM199801223380415
- Wilholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol. 1993:44:589-591. http://www.ncbi.nlm.nih.gov/pubmed/8405019
- Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995:18(6):779-784. http://care.diabetesjournals.org/content/18/6/779.full.pdf
- Brown JB, Pedula K, Barzilay J, Herson MK, Latare P. Lactic acidosis rates in type 2 diabetes. Diabetes Care. 1998:21(10):1659–1663. http://care.diabetesjournals.org/content/21/10/1659.full.pdf
- 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. 2010 April 14 (4):CD002967. http://www.ncbi.nlm.nih.gov/pubmed/12076461
- 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. 2008:31(11):2086-2091. http://www.ncbi.nlm.nih.gov/pubmed/18782901
- Khurana R, Malik IS. Metformin: safety in cardiac patients. Postgrad Med J. 2010:86:371-373. http://www.ncbi.nlm.nih.gov/pubmed/19564648
- Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012:35(4):731-737. http://www.ncbi.nlm.nih.gov/pubmed/22442396
- Roussel R, Travert F, Pasquet B, et al. Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010:170(21):1892-1899. http://www.ncbi.nlm.nih.gov/pubmed/21098347
- Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ. 2007:335(7618):497. http://www.ncbi.nlm.nih.gov/pubmed/17761999
- Willfort-Ehringer A, Ahmadi R, Gessl A, et al. Neointimal proliferation within carotid stents is more pronounced in diabetic patients with initial poor glycaemic state. Diabetologia. 2004:47(3):400–406. http://www.ncbi.nlm.nih.gov/pubmed/14985968
- Timmer JR, Ottervanger JP, de Boer MJ, et al. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2005:45(7):999–1002. http://www.ncbi.nlm.nih.gov/pubmed/15808754
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015:38(1):140-149. http://care.diabetesjournals.org/content/38/1/140.extract
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-865. http://www.ncbi.nlm.nih.gov/pubmed/9742977