Use of Metformin in the Setting of Mild-To-Moderate Renal Insufficiency

Reviews/Commentaries/ADA Statements REVIEW Use of Metformin in the Setting of Mild-to-Moderate Renal Insufficiency 1 KASIA J. LIPSKA, MD hepatic gluconeogenesis without raising 2 CLIFFORD J. BAILEY, PHD, FRCP fi 3 insulin levels, it rarely leads to signi cant SILVIO E. INZUCCHI, MD hypoglycemia when used as a monother- apy (8,11). As a result, metformin is widely considered an ideal first-line agent for the treatment of type 2 diabetes, as common clinical conundrum faces despite multiple trials of intensive glu- recommended by several clinical guide- all U.S. practitioners treating pa- cose control using a variety of glucose- lines (12–14). A fi tients with type 2 diabetes. Today’s lowering strategies, there is a paucity of In addition to such bene ts, metfor- U.S. Food and Drug Administration pre- data to support specificadvantageswith min reduces the risk of developing di- scribing guidelines for metformin contra- other agents on cardiovascular outcomes abetes in individuals at high risk for the indicate its use in men and women with (5–7). disease (15) and has been considered as a serum creatinine concentrations $1.5 In the original UK Prospective Di- reasonable “off-label” approach in se- and $1.4 mg/dL ($132 and $123 abetes Study (UKPDS), 342 overweight lected individuals for diabetes prevention mmol/L), respectively. In a patient toler- patients with newly diagnosed diabetes (16). ating and controlled with this medication, were randomly assigned to metformin should it automatically be discontinued therapy (8). After a median period of 10 — as the creatinine rises beyond these cut years, this subgroup experienced a 39% HISTORICAL PERSPECTIVE De- fi points over time? Stopping metformin of- (P = 0.010) risk reduction for myocardial spite these proven bene ts, metformin ten results in poorly controlled glycemia infarction and a 36% reduction for total remains contraindicated in a large seg- and/or the need for other agents with their mortality (P = 0.011) compared with con- ment of the type 2 diabetic population, own adverse-effect profiles. Moreover, is ventional diet treatment. Similar benefits largely because of concerns over the rare the now widespread use of estimated glo- were not observed in those randomly as- adverse effect of lactic acidosis. For these merular filtration rate (eGFR) in lieu of signed to sulfonylurea or insulin. In an reasons, the drug has been restricted to serum creatinine levels creating even 8.5-year posttrial monitoring study, after individuals with normal creatinine levels more confusion, especially in those with participants no longer were randomly as- as a surrogate for renal competence. abnormalities in one but not the other in- signed to their treatments, individuals Other contraindications (e.g., any signif- direct measure of renal function? Indeed, originally assigned to metformin (n = icant hypoxemia, alcoholism, cirrhosis, a more than a decade and a half after met- 279) continued to demonstrate a reduced recent radiocontrast study) also increase formin became available in the U.S., de- risk for both myocardial infarction (rela- the risk for or the consequences of lactic bate continues over the best approach in tive risk 33%, P = 0.005) and total mor- acidosis, but these are not the topic of this these settings (1–3). How many patients tality (relative risk 27%, P = 0.002) (9). review. are unable to receive this medication on The latter results are even more impres- Metformin belongs to the biguanide drug class (previous members include the basis of guidelines which, although sive when one considers that HbA1c levels well intentioned, are somewhat arbitrary in all initially randomly assigned groups phenformin and buformin), developed and outdated based on modern assess- had converged within 1 year of follow-up. for lowering glucose in the 1950s. Initial ments of renal status? Unlike sulfonylureas, thiazolidine- enthusiasm for biguanides was tempered diones, and insulin, metformin is weight over the next two decades by the growing ADVANTAGES OF neutral (10), which makes it an attractive recognition of their risk of lactic acidosis. METFORMIN—Thereissomeevi- choice for obese patients. Furthermore, A marked reduction in biguanide use dence that early treatment with metformin the management of type 2 diabetes can occurred in the mid-1970s because phen- is associated with reduced cardiovascular be complicated by hypoglycemia, which formin, extensively adopted in clinical morbidity and total mortality in newly can seriously limit the pursuit of glycemic practice, was implicated in a number of diagnosed type 2 diabetic patients (4). control. Here, too, metformin has advan- fatal cases of this severe metabolic de- However, the data come from a small sub- tages over insulin and some types of in- compensation (17). The association with group of a much larger trial. In contrast, sulin secretagogues; by decreasing excess lactic acidosis eventually led to its with- drawal from the market. Importantly, lac- ccccccccccccccccccccccccccccccccccccccccccccccccc tic acidosis with phenformin seems to occur ~10–20 times more frequently From the 1Robert Wood Johnson Clinical Scholars Program, Yale University School of Medicine, New Haven, Connecticut; the 2Department of Life and Health Sciences, Aston University, Birmingham, U.K.; and the than with metformin (18). In contrast to 3Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut. metformin, modestly raised phenformin Corresponding author: Silvio E. Inzucchi, [email protected]. concentrations may reduce peripheral Received 15 December 2010 and accepted 16 March 2011. glucose oxidation and enhance peripheral DOI: 10.2337/dc10-2361 © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly lactate production, which can increase cir- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ culating lactate levels. In fact, phenformin licenses/by-nc-nd/3.0/ for details. levels correlate with lactate concentration, care.diabetesjournals.org DIABETES CARE, VOLUME 34, JUNE 2011 1431 Metformin in renal insufficiency whereas metformin levels do not (19). In updated clinical practice guidelines is- intestine and salivary glands as well as addition, ~10% of European Caucasians sued by the American Diabetes Associa- in the kidney (25). It has a plasma elimina- have an inherent defect in phenformin hy- tion, for example, do not actually discuss tion half-life of 6.2 h and is renally elimi- droxylation, which may lead to drug accu- renal thresholds (16) but refer the reader nated both by filtration and active tubular mulation and, as a result, elevated lactate to a separate consensus statement for pre- secretion (26). levels (20). scribing details. This statement, authored In careful experiments, Tucker et al. The experience with phenformin re- by members of the American Diabetes As- (27) studied metformin kinetics in 4 sulted in cautious use of metformin in sociation and European Association for healthy subjects and 12 type 2 diabetic Europe. In the 1980s, the creatinine cut the Study of Diabetes, reports that met- subjects and found that plasma renal points for contraindication to metformin formin seems safe unless eGFR falls to clearance of metformin highly correlated were considered to be appropriate at 1.4 ,30 mL/min per 1.73 m2 (12). with creatinine clearance (CrCl; r = 0.85, mg/dL in women and 1.5 mg/dL in men. Clinical guidelines outside of the U.S. P , 0.001). However, the relationship This was based on the calculated ability to incorporate the eGFR for determination between physiological clearance of an ac- remove 3 g of metformin (an amount of metformin safety. In the U.K., for tual oral dose and CrCl was much weaker slightly beyond the maximum daily U.S. example, prescribing guidelines consider (r = 0.66, P , 0.01). Therefore, the inves- dose) at steady-state levels within 24–48 h. both creatinine and eGFR for assessing tigators postulated that other factors may In fact, the ability to comfortably remove treatment eligibility. The National Insti- impact this relationship, such as perhaps the drug extends up to creatinine levels of tute for Health and Clinical Excellence gastrointestinal absorption of metformin 1.8–2.0 mg/dL, but the cut points chosen recommends reviewing the clinical cir- in patients with renal failure and/or non- were intentionally set lower to ensure that cumstances when serum creatinine ex- renal clearance of a small amount of the those patients who may be lost to follow- ceeds 130 mmol/L (1.5 mg/dL) or eGFR drug. up and whose creatinine levels increase falls below 45 mL/min per 1.73 m2.The In another pharmacokinetic study (28), over time would not be at risk for appre- National Institute for Health and Clinical asingle850-mgdoseofmetforminwas ciable drug accumulation. Excellence further specifies that metfor- given to 21 healthy subjects and 13 subjects Metformin was not approved in the min be stopped if serum creatinine ex- with renal insufficiency (mild to severe). U.S. until December of 1994 and was ceeds 150 mmol/L (1.7 mg/dL) (a higher In the control group (data presented are marketed in 1995. The experience with threshold than in the U.S.) or eGFR is be- mean 6 SD) (mean CrCl 112 6 8mL/min), phenformin led to judicious labeling and low 30 mL/min per 1.73 m2 (14). In con- average renal metformin clearance was recommendations for careful monitoring trast, the Canadian Diabetes Association 636 6 84 mL/min, whereas in mild chronic of adverse events. Its new-drug applica- practice guidelines are now based solely kidney disease (CKD) (CrCl 61–90 mL/min; tion was the subject of extensive review. on eGFR, recommending caution with mean 73 6 7) clearance was reduced at The risk for lactic acidosis was estimated eGFR ,60 mL/min per 1.73 m2 and con- 384 6 122 mL/min.

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