Metformin And Renal Function
etformin is first-line therapy for the management of type 2 diabetes mellitus, based on the American Diabetes Association and American College of Clinical Endocrinology guidelines. Unless there is a contraindication, metformin should be considered part of a patient’s regimen for type 2 diabetes mellitus. A controversial contraindication for metformin is renal disease or dysfunction. Absolute cut-offs in serum creatinine has been published as times to discontinue metformin therapy (≥1.4 mg/dL for women; ≥1.5 mg/dL for men). Lipska KL, et al, published recommendations for metformin among patients with mild to moderate renal dysfunction. This publication has been used in clinical practice to support “relaxed” dosing of metformin. Based on this publication in Diabetes Care (2011), the following recommendations were suggested: For patients with estimated glomerular filtration rate (eGFR) above 60, then metformin can be continued and renal function should be monitored on an annual basis. For patients with eGFR between 45 and 60, then metformin can be continued but the frequency of monitoring increases to every 3 or 6 months. For patients with eGFR between 30 and 45, there are several options depending on the individual. These options include lowering the dose by 50%; increasing the monitoring of renal function; or discontinuing metformin. For patients with a baseline eGFR 30 and 45, metformin should not be initiated. For patients with eGFR less than 30, then metformin should be stopped (if prescribed) or not initiated (if considered for new patients). As diabetes educators, it is essential to check package inserts and/or drug references for the method (CrCl or eGFR) to assess renal function and appropriate dose adjustments. On Friday, April 8, the Food and Drug Admi Continue reading >>
Metformin Use Being Limited?
Current black box warning may be overstating the kidney risk. Metformin—the blockbuster drug utilized as the primary agent to treat patients with type 2 diabetes—may potentially be hindered in usage due to its current prescribing grounds. Despite its establishment as the first-line therapy for type 2 diabetes, about one-half of the patients currently in the United States do not take it. A major proponent of this is its current labeling, which expresses unjustifiable concerns about its use for treatment in those with mild to moderate renal insufficiency. The current label carries a contraindication against use of metformin when serum creatinine levels exceed 1.4mg/dL in women or 1.5mg/dL in men. Over the past few years, clinicians throughout the country have come to an overwhelming consensus that the US Food and Drug Administration (FDA) labeling for metformin could be more lenient and also that it can be expressed in the more precise estimated glomerular filtration rates (eGFRs), rather than serum creatinine. The FDA’s initial rationale behind the label was due to resilient evidence that phenformin caused lactic acidosis (another biguanide which has been removed from the US market). Metformin is cleared from the body via the kidneys and for patients with significant renal failure, there were increasing concerns that metformin could potentially build up to relatively high levels that could leave patients to have lactic acidosis. There is now an overwhelming two decades’ worth of research and evidence showing no serious increased risks for lactic acidosis in patients with mild-to-moderately impaired renal function. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have furthermore supported the removal of restric Continue reading >>
Changes In Metformin Use In Chronic Kidney Disease
Go to: Fear of LA Metformin is chemically similar to phenformin, but has a different mechanism of action. Although the fear of LA remains, no absolute definitive causal relationship has been proven beyond doubt. Many reported cases of metformin-associated LA (MALA) did not measure metformin levels, whereas in others levels were not high, suggesting ‘metformin coincident lactic acidosis’ [9]. In 1998, Misbin et al. reported that after starting to use metformin, rates of LA in the USA were no different from prior to the approval of metformin [10]. Many reported cases of LA had multiple risk factors besides renal failure. Since DM2 is a risk factor, it is thought that many such cases may have been just from DM2. The putative risk factors for LA described in the literature include old age, decreased cardiac output, respiratory failure or hypoxic conditions, ethanol intoxication, fasting and decreased hepatic function. In a nested case–control analysis that included 50 048 patients, six patients were identified with active use of metformin and LA. Out of those, five patients had sepsis and signs of end-organ damage, suggesting that LA most frequently occurs in acutely worsening clinical scenarios [11]. Continue reading >>
Kidney Function Cutoffs For Safe Metformin Use
Volume: 46 Urologic Diseases The risk of complications (such as lactic acidosis) that can be associated with metformin increases in patients with renal insufficiency. At what creatinine clearance should this agent be discontinued? — Ivanka Vassileva, MD Lawton, Okla Currently, the contraindication for metformin use in patients with renal insufficiency is rigidly defined as a serum creatinine level of 1.5 mg/dL or higher in men and 1.4 mg/dL or higher in women. As you know, the serum creatinine level is often not a precise indicator of renal function. Measuring creatinine clearance, which is most often done using the Modification of Diet in Renal Disease (MDRD) equation, is probably a better way to assess for renal insufficiency. Current prescribing guidelines suggest confirming that creatinine clearance is normal in older persons and in others in whom the serum creatinine level may be misleading. Metformin appears to accumulate once the creatinine clearance falls below 60 mL/min. Thus, it would be unwise to use metformin in any patient whose creatinine clearance is lower than this. — Silvio Inzucchi, MD Professor of Medicine Division of Endocrinology Yale University School of Medicine New Haven, Conn Continue reading >>
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Why Is Metformin Contraindicated In Chronic Kidney Disease?
To the Editor: In their article about the care of patients with advanced chronic kidney disease, Sakhuja et al1 mentioned that metformin is contraindicated in chronic kidney disease. Metformin is a good and useful drug. Not only is it one of the cheapest antidiabetic medications, it is the only one shown to reduce cardiovascular mortality rates in type 2 diabetes mellitus. Although metformin is thought to increase the risk of lactic acidosis, a Cochrane review2 found that the incidence of lactic acidosis was only 4.3 cases per 100,000 patient-years in patients taking metformin, compared with 5.4 cases per 100,000 patient-years in patients not taking metformin. Furthermore, in a large registry of patients with type 2 diabetes and atherothrombosis,3 the rate of all-cause mortality was 24% lower in metformin users than in nonusers, and in those who had moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m2) the difference was 36%.3 A trial by Rachmani et al4 raised questions about the standard contraindications to metformin. The authors reviewed 393 patients who had at least one contraindication to metformin but who were receiving it anyway. Their serum creatinine levels ranged from 1.5 to 2.5 mg/dL. There were no cases of lactic acidosis reported. The patients were then randomized either to continue taking metformin or to stop taking it. At 2 years, the group that had stopped taking it had gained more weight, and their glycemic control was worse. In the Cochrane analysis,2 although individual creatinine levels were not available, 53% of the studies reviewed did not exclude patients with serum creatinine levels higher than 1.5 mg/dL. This equated to 37,360 patient-years of metformin use in studies that included patients with chronic kidney disease, and did Continue reading >>
In Brief: New Recommendations For Use Of Metformin In Renal Impairment
The FDA has required labeling changes that replace serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) as the parameter used to determine the appropriateness of treatment with the biguanide metformin (Glucophage, and others) in patients with renal impairment. These changes will allow more patients with mild to moderate renal impairment to receive metformin, which is generally the first drug prescribed for treatment of type 2 diabetes. Metformin was previously contraindicated in women with a SCr level ≥1.4 mg/dL and in men with a SCr level ≥1.5 mg/dL, but use of SCr as a surrogate indicator tends to underestimate renal function in certain populations (e.g., younger patients, men, black patients, patients with greater muscle mass). The calculation of eGFR takes into account age, race, and sex, as well as SCr level, providing a more accurate assessment of kidney function. A literature review summarized in an FDA Drug Safety Communication concluded that, based on eGFR, metformin is safe to use in patients with mild renal impairment and in some patients with moderate renal impairment.1 The eGFR should be calculated before patients begin treatment with metformin and at least annually thereafter. Metformin is now contraindicated in patients with an eGFR <30 mL/min/1.73 m2, and starting treatment with the drug in patients with an eGFR between 30 and 45 mL/min/1.73 m2 is not recommended. If the eGFR falls below 45 mL/min/1.73 m2 in a patient already taking metformin, the benefits and risks of continuing treatment should be assessed. Metformin should be not be administered for 48 hours after an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m2 or a history of liver disease, alcoholism, or heart failure, or in those receiving Continue reading >>
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Fda Issues Guidance For Metformin Use In Renal Impairment
Chris Tanski received his PharmD from the University at Buffalo School of Pharmacy and Pharmaceutical Sciences and is now working as a clinical staff pharmacist for Pinnacle Health in Harrisburg, Pennsylvania. He entered the field of hospital pharmacy directly from school, and he was one of the first to pilot a decentralized pharmacist role in the hospital. His other notable work contributions include working on palliative projects and transition of care for COPD patients. Chris was an editor and contributor to a film theory blog, a sketch comedy writer throughout pharmacy school, and he has a significant amount of experience writing drug information papers on neurology and infectious disease topics for both school and work. The FDA has issued new guidance for the use of the first-line diabetes drug metformin in patients with renal impairment. Metformin was approved by the FDA in 1994 for the management of type 2 diabetes. Since its approval, its labeling has warned of a contraindication in elevated serum creatinine (>1.5 mg/dL for males, >1.4 mg/dL for females) due to a risk of lactic acidosis secondary to metformin accumulation.1 Other risk factors for lactic acidosis include contrast dye exposure within 48 hours, chronic or excessive alcohol intake, dehydration, sepsis, acute congestive heart failure, and age. This absolute contraindication was based on clinical trials of an older biguanide called phenformin, which showed a greater risk of lactic acidosis associated with significant mortality and was subsequently pulled off the market in 1977.2 Although phenformin is no longer available in the United States, it’s still available in European and South American markets. Notably, the incidence of lactic acidosis associated with metformin is as low as 0.03 cases per 10 Continue reading >>
Metformin - Glucophage - Renal Dosing
Usual starting dose: 500mg po bid or 850 mg po qd. Dosage increases should be made in increments of 500 mg weekly or 850 mg q2 weeks, up to a total of 2000 mg per day, given in divided doses. (Maximum: 2550mg/day). Glucophage XR: Starting dose: 500 mg qd with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg daily with the evening meal. Contraindicated: Males with a serum creatinine > 1.5 mg/dl or females >1.4 mg/dl. Also patients with an abnormal creatinine clearance (~ <60-70 ml/min). National Institutes of Health, U.S. National Library of Medicine, DailyMed Database. Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates. A local search option of this data can be found here . The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinicaljudgment. Neither GlobalRPh Inc. nor any other party involved in thepreparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. Readthe disclaimer Continue reading >>
Metformin In Patients With Type 2 Diabetes And Kidney Disease
Go to: Abstract Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies d Continue reading >>
Use Of Metformin In The Setting Of Mild-to-moderate Renal Insufficiency
ADVANTAGES OF METFORMIN There is some evidence that early treatment with metformin is associated with reduced cardiovascular morbidity and total mortality in newly diagnosed type 2 diabetic patients (4). However, the data come from a small subgroup of a much larger trial. In contrast, despite multiple trials of intensive glucose control using a variety of glucose-lowering strategies, there is a paucity of data to support specific advantages with other agents on cardiovascular outcomes (5–7). In the original UK Prospective Diabetes Study (UKPDS), 342 overweight patients with newly diagnosed diabetes were randomly assigned to metformin therapy (8). After a median period of 10 years, this subgroup experienced a 39% (P = 0.010) risk reduction for myocardial infarction and a 36% reduction for total mortality (P = 0.011) compared with conventional diet treatment. Similar benefits were not observed in those randomly assigned to sulfonylurea or insulin. In an 8.5-year posttrial monitoring study, after participants no longer were randomly assigned to their treatments, individuals originally assigned to metformin (n = 279) continued to demonstrate a reduced risk for both myocardial infarction (relative risk 33%, P = 0.005) and total mortality (relative risk 27%, P = 0.002) (9). The latter results are even more impressive when one considers that HbA1c levels in all initially randomly assigned groups had converged within 1 year of follow-up. Unlike sulfonylureas, thiazolidinediones, and insulin, metformin is weight neutral (10), which makes it an attractive choice for obese patients. Furthermore, the management of type 2 diabetes can be complicated by hypoglycemia, which can seriously limit the pursuit of glycemic control. Here, too, metformin has advantages over insulin and some Continue reading >>
Metformin Contraindications
The biguanide metformin (dimethylbiguanide) was initially introduced for use in the treatment of type 2 diabetes mellitus in the late 1950s. Today this drug is considered to be the first-choice agent and the “gold standard” for most people with type 2 diabetes. It has been estimated that the annual number of people receiving prescriptions for metformin worldwide is more than 120 million. The efficacy and benefits of metformin treatment in type 2 diabetes have been confirmed by large-scale studies and recognized by many consensus statements. Still, a large list of contraindications may increase the incidence of serious adverse effects, which precludes many patients from taking metformin. Intolerance and contraindications to metformin Three particular contraindications to the use of metformin have been suggested. They include renal impairment with elevated serum creatine levels (i.e. more than 136 mmol/l in men and 124 mmol/l in women) or abnormal creatinine clearance, congestive heart failure requiring pharmacologic treatment and advanced age (more than 80 years of age). Renal impairment represents a contraindication to metformin usage due to the increased risk of lactic acidosis (a form of metabolic acidosis due to the inadequate clearance of lactic acid from the blood). Although lactic acidosis linked to metformin is a rare condition, with an estimated prevalence of one to five cases per 100 000 population, it has a reported mortality of 30-50%. However, recent studies have suggested that metformin can be used safely, unless the estimated glomerulal filtration rate (the volume of fluid that is filtered from the capillaries of the glomeruli into the kidney tubules per unit time) falls below 30 ml/min, with a dose reduction advised at 45 ml/min. Congestive heart fail Continue reading >>
Using Metformin In The Presence Of Renal Disease
Using metformin in the presence of renal disease Using metformin in the presence of renal disease BMJ 2015; 350 doi: (Published 14 April 2015) Cite this as: BMJ 2015;350:h1758 Tahseen A Chowdhury, consultant in diabetes, M Magdi Yaqoob, professor in clinical nephrology 1Departments of Diabetes and Nephrology, Barts and the London School of Medicine and Dentistry, London E1 1BB, UK. Correspondence to: T Chowdhury Tahseen.Chowdhury{at}bartshealth.nhs.uk Current guidelines are too restrictive, and many patients who could benefit are missing out In January, the electronic Medicines Compendium (eMC) updated the Summary of Product Characteristics for Glucophage (metformin), approved by the UK Medicines and Healthcare Products Regulatory Agency (MHRA). The summary states that Metformin may be used in patients with moderate renal impairment, stage 3a (creatinine clearance [CrCl] 45-59 mL/min or estimated glomerular filtration rate [eGFR] 45-59 mL/min/1.73 m2) only in the absence of other conditions that may increase the risk of lactic acidosis . . . If CrCl or eGFR fall <45 mL/min or <45 mL/min/1.73 m2 respectively, metformin must be discontinued immediately.1 This is reiterated in the patient information leaflet. Interestingly, the summary for generic metformin states that Renal failure or renal dysfunction (creatinine clearance <60 ml/min) is a contraindication to use. In the face of burgeoning levels of type 2 diabetes and associated renal disease, we believe that this restriction is too conservative and will deny an important drug to many thousands of people with diabetes who Continue reading >>
Use Of Metformin In The Setting Of Mild-to-moderate Renal Insufficiency
Go to: HISTORICAL PERSPECTIVE Despite these proven benefits, metformin remains contraindicated in a large segment of the type 2 diabetic population, largely because of concerns over the rare adverse effect of lactic acidosis. For these reasons, the drug has been restricted to individuals with normal creatinine levels as a surrogate for renal competence. Other contraindications (e.g., any significant hypoxemia, alcoholism, cirrhosis, a recent radiocontrast study) also increase the risk for or the consequences of lactic acidosis, but these are not the topic of this review. Metformin belongs to the biguanide drug class (previous members include phenformin and buformin), developed for lowering glucose in the 1950s. Initial enthusiasm for biguanides was tempered over the next two decades by the growing recognition of their risk of lactic acidosis. A marked reduction in biguanide use occurred in the mid-1970s because phenformin, extensively adopted in clinical practice, was implicated in a number of fatal cases of this severe metabolic decompensation (17). The association with lactic acidosis eventually led to its withdrawal from the market. Importantly, lactic acidosis with phenformin seems to occur ~10–20 times more frequently than with metformin (18). In contrast to metformin, modestly raised phenformin concentrations may reduce peripheral glucose oxidation and enhance peripheral lactate production, which can increase circulating lactate levels. In fact, phenformin levels correlate with lactate concentration, whereas metformin levels do not (19). In addition, ~10% of European Caucasians have an inherent defect in phenformin hydroxylation, which may lead to drug accumulation and, as a result, elevated lactate levels (20). The experience with phenformin resulted in cautiou Continue reading >>
Metformin Use In Renal Impairment Extended
For patients with a creatinine clearance of 45–59ml/min or an eGFR of 45–59ml/min/1.73m2, the initial dose of metformin is 500mg or 850mg once daily in the morning with food. The maximum daily dose is 1g in two divided doses with monitoring of renal function every 3–6 months. This change to the prescribing information reflects the advice given in the NICE clinical guideline on the management of type II diabetes, namely that metformin can be used with caution in patients with renal impairment but the dose should be reviewed if the patient's eGFR drops below 45ml/min/1.73m2 and treatment discontinued if the eGFR drops below 30ml/min/1.73m2. The metformin drug entry in MIMS has been updated to reflect the current Glucophage SPCs. The MIMS drug listings for products containing metformin in combination with other drugs (eg, dipeptidyl peptidase 4 inhibitors, SGLT2 inhibitors, pioglitazone) will be updated when the updated SPCs become available. Prescribers should refer to the product SPCs to check if a combination product is suitable for an individual patient with renal impairment. Follow MIMS on Twitter Continue reading >>
