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Metformin In Acute Renal Failure

Metformin And Acute Kidney Injury: Is It The Culprit?

Metformin And Acute Kidney Injury: Is It The Culprit?

Endocrine Abstracts (2014) 34 P251 | DOI: 10.1530/endoabs.34.P251 Metformin and acute kidney injury: is it the culprit? Blackpool Victoria Hospital, Blackpool, UK. Three people (two males), with mean age (range) 65 (4975) years, presented as emergencies with acute renal failure (AKI). They had type 2 diabetes mellitus, with mean duration 7 (212) years. All three were taking anti-hypertensive therapy: two were on ramipril and one on losartan and indapamide. All three were taking metformin with mean daily dose 2.6 (1.73.0) g. All three patients had mild renal impairment (CKD stage 3), but renal function was stable 23 months before presentation with mean blood urea 8.1 (5.69.5) mmol/l, creatinine 118 (108133) mol/l and eGFR 49 (4359) ml/min per l. They presented with a 1 week history of symptoms including vomiting (2), diarrhoea (2), unsteadiness (3), confusion (1), and falls (2). On admission the mean blood glucose was 8.5 (4.913.0) mmol/l, urea 32 (22 42) mmol/l, and creatinine 763 (652978)mol/l. They were acidotic with mean pH 7.19 (7.157.23), bicarbonate 15.6 (10.321.2) mmol/l, and lactate 3.6 (2.05.9) mmol/l. The mean blood metformin level was raised at 12.2 (11.014.3) mg/l. The accepted therapeutic range is 0.52.0 mg/l). Metformin, ramipril, losartan and indapamide were discontinued. One patient required haemofiltration but in all three urine output soon improved with i.v. fluid therapy. Renal function was back to baseline 23 months later with mean blood urea 7.5 (6.88.4) mmol/l, creatinine 113 (104131) mol/l and eGFR 52 (4560) ml/min per l. Metformin is eliminated, unchanged, by renal excretion. We suggest that inappropriately high metfomin doses in these patients with mild renal impairment has led to escalating blood metformin levels, which in turn largely account Continue reading >>

Risks Of Metformin In Type 2 Diabetes And Chronic Kidney Disease: Lessons Learned From Taiwanese Data

Risks Of Metformin In Type 2 Diabetes And Chronic Kidney Disease: Lessons Learned From Taiwanese Data

Abstract Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with metformin-associated lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted metformin use, including a 35% higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other biguanides, phenformin and buformin, suggest that the recent relaxation of FDA recommendations to expand metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates ≥30 instead of our recommended ≥45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time. Continue reading >>

Metabolic Effects Of Metformin In Patients With Acute Renal Failure

Metabolic Effects Of Metformin In Patients With Acute Renal Failure

Metformin use has been associated with significant disturbances in acid-base balance. Metformin remains the first-line therapy for majority of patients with type 2 diabetes mellitus. Its metabolic effects have provided great support for its use in diabetes management. However, risks of renal impairment and lactic acidosis have always warranted close monitoring in patients with predisposing factors to these events. In fact, lactic acidosis has been associated with renal impairment. Metformin is not metabolized in the liver and is excreted by active tubular secretion. The risk of developing lactic acidosis greatly depends on the magnitude of each patient’s renal impairment and their age. Nonetheless, these studies fail to take into consideration those patients with renal failure. The majority of trials out there exclude patients with renal defects due to its nephrotoxic potential. The nephrotoxicity of increased levels of metformin relies on its effect on renal mitochondrial activity. Previous studies have demonstrated that therapeutic doses of metformin are not associated with risk of lactic acidosis. Renal mitochondrial dysfunction can lead to tubular cell ischemia and increased lactic acid production. Hence, those patients with renal impairment will warrant closer monitoring and dose optimization strategies to prevent these complications while obtaining optimal glucose control. Recently, renal dose adjustments changed. Now patients are to be monitored based on glomerular filtration rate and not serum creatinine for metformin therapy. A recent study conducted by David Cucchiari and colleagues evaluated the dose-related effects of metformin on acid-base balance in patients with diabetes who develop acute renal failure. In this cross-sectional study, 126 patients were i Continue reading >>

Use Of Metformin In The Setting Of Mild-to-moderate Renal Insufficiency

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-associated Acute Kidney Injury And Lactic Acidosis

Metformin-associated Acute Kidney Injury And Lactic Acidosis

Copyright © 2011 David Arroyo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Objectives. Metformin is the preferred oral antidiabetic agent for type 2 diabetes. Lactic acidosis is described as a rare complication, usually during an acute kidney injury (AKI). Material and Methods. We conducted a prospective observational study of metformin-associated AKI cases during four years. 29 cases were identified. Previous renal function, clinical data, and outcomes were recorded. Results. An episode of acute gastroenteritis precipitated the event in 26 cases. Three developed a septic shock. Three patients died, the only related factor being liver dysfunction. More severe metabolic acidosis hyperkalemia and anemia were associated with higher probabilities of RRT requirement. We could not find any relationship between previous renal dysfunction and the outcome of the AKI. Conclusions. AKI associated to an episode of volume depletion due to gastrointestinal losses is a serious complication in type 2 diabetic patients on metformin. Previous renal dysfunction (mild-to-moderate CKD) has no influence on the severity or outcome. 1. Introduction Metformin is the only biguanide extensively used these days, and has become the first-line oral drug in type 2 diabetes [1]. Metformin-associated lactic acidosis has not been thoroughly characterized. Meta-analyses and large studies have been unable to establish an epidemiological association, probably due to its low incidence rate. However, most cases have been reported associated with an episode of acute kidney injury (AKI), predominantly in intensive care units [ Continue reading >>

Metformin - Renal Impairment And Risk Of Lactic Acidosis

Metformin - Renal Impairment And Risk Of Lactic Acidosis

Publications Key Messages Metformin is generally considered to be first line treatment for type 2 diabetes mellitus. The most important adverse effect is lactic acidosis due to the high fatality rate. Renal impairment is a risk factor for the development of lactic acidosis in patients taking metformin. Metformin can still be used in patients with stable renal impairment but the dose MUST be reduced. Patients should be advised to seek medical attention if they experience symptoms of lactic acidosis or acute kidney injury. Metformin is recommended as the first line oral hypoglycaemia medicine for patients with type 2 diabetes in international guidelines1. However, use has been restricted in patients with renal impairment due to the increased risk of lactic acidosis. The New Zealand metformin data sheets have recently been updated to allow for the use of metformin in patients with stable renal impairment. The contraindication cut-off level for creatinine clearance has changed from <60 mL/min to <15 mL/min. Patients with renal impairment MUST take a lower dose of metformin to avoid toxic concentrations. The maximum daily dose to be used in renal impairment is specified in the metformin data sheet, according to degree of impairment. The metformin data sheets can be found on the Medsafe website (www.medsafe.govt.nz/Medicines/infoSearch.asp). Lactic acidosis Lactate is produced by most tissues and is rapidly cleared by the liver. Levels of lactate increase as a consequence of intracellular acidosis and help to slow down the onset of acidosis. High lactate levels are generally considered to be those above 4 mmol/L2. Lactic acidosis is a condition of high lactate and a pH below 7.352. There are many causes of elevated lactate including2: sepsis and septic shock regional tissue i Continue reading >>

Prolonged Hemodialysis For Severe Metformin Intoxication

Prolonged Hemodialysis For Severe Metformin Intoxication

Prolonged Hemodialysis for Severe Metformin Intoxication Lactic acidosis is a rare and often lethal complication of metformin therapy. We describe a patient who ingested at least 52 g, and possibly more, of metformin and presented with severe lactic acidosis and acute renal failure. He was treated with prolonged hemodialysis: a 3.5 h treatment that did not result in significant clinical improvement, followed by an additional 31 h treatment. With this treatment regimen, his lactate levels gradually decreased and his clinical status improved. A metformin level drawn approximately 25 h after the initiation of the second hemodialysis treatment was still elevated at about five times the upper therapeutic limit. It is suggested that prolonged dialysis is indicated in patients with severe metformin overdose, particularly those with renal failure. In patients whose cardiovascular status permits, prolonged hemodialysis should be strongly considered. Keywords: Metformin , hemodialysis , diabetes mellitus , intoxication , renal failure Metformin is a biguanide oral antihyperglycemic agent that has been used for over three decades worldwide and the United States since 1995 for the treatment of type 2 diabetes mellitus. Its primary mechanisms of action appear to be suppression of gluconeogenesis and enhancement of peripheral glucose utilization. It was the most prescribed antidiabetic medication in the United States in the year 2000. 1 Barrueto F, Meggs WJ, Barchman MJ. Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol. 2002;40:177180. [Taylor & Francis Online] , [Google Scholar] It has been recommended as the drug of first choice in patients diagnosed with type 2 diabetes in a consensus document issued by the American Diabetic Association and the Europea Continue reading >>

Changes In Metformin Use In Chronic Kidney Disease

Changes In Metformin Use In Chronic Kidney Disease

Background Glucose-lowering biguanides were discovered in the 1920s. One of these was metformin (dimethylbiguanide), but it was then forgotten [1]. The first human trial on biguanides that used the name Glucophage (glucose eater) was published in 1957 [2]. In the next couple of years reports were published on phenformin [3] and buformin [4]. However, due to their association with lactic acidosis (LA), both phenformin and buformin were withdrawn from many countries. Similar concerns were raised for metformin, but it remained on the market and has been available in the UK since 1958, although it only became available in the USA in 1994. Clinical benefits in diabetes mellitus type 2 Metformin acts primarily in the liver by reducing glucose output and also by enhancing peripheral uptake of glucose, mainly in muscles. It is not generally associated with a risk of hypoglycemia unless there is excessive exercise, severe calorie reduction or when mixed with other antidiabetic medicine. There is absence of weight gain along with modest reductions in triglycerides [5]. It causes a reduction in mortality by decreasing cardiovascular complications [6]. Metformin has shown some effectiveness in polycystic ovarian syndrome, some gynecological cancers, nonalcoholic fatty liver disease and for premature puberty. However, its main role remains in the management of diabetes mellitus type 2 (DM2). The International Diabetes Federation lists it as one of the first antidiabetic medicines to be used for DM2 [7]. The World Health Organization lists it as one of two essential medicines for diabetes [8]. 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 be Continue reading >>

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As you were browsing PracticeUpdate, something about your browser made us think you were a bot. There are a few reasons this might happen: You're a power user moving through this website with super-human speed. You've disabled JavaScript in your web browser. A third-party browser plugin, such as Ghostery or NoScript, is preventing JavaScript from running. Additional information is available in this . After completing the CAPTCHA below, you will immediately regain access to PracticeUpdate. ​ You reached this page when attempting to access from 35.226.183.143 on 2018-01-06 18:18:13 UTC. Trace: 8d3497e3-c874-476e-b444-70710053403c via f142fe30-0da7-428a-92b2-8a74e399b4ec Continue reading >>

Fda Issues Guidance For Metformin Use In Renal Impairment

Fda Issues Guidance For Metformin Use In Renal Impairment

FDA Issues Guidance for Metformin Use in Renal Impairment 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, its 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 1000 patient-years. The FDA reviewed several studies to determine whether patients with mild to moderate renal impairment could safely continue on metformin to manage their type 2 diabetes. One of the larger trials reviewed was an observational study of 51,675 type 2 diabetes patients to determine the effect metformin would have on primary outcomes of cardiovascular disease (CVD), all-cause mortality, and acidosis or serious infections with varying degrees of renal function.3 Based on subgroup analyses of patients with varying degrees of renal impairment, the investigators determined that patients with an estimated glomerular filtration rate (eGFR) >45 mL/min/m2 showed no Continue reading >>

Risk Of Acute Kidney Injury And Survival In Patients Treated With Metformin: An Observational Cohort Study

Risk Of Acute Kidney Injury And Survival In Patients Treated With Metformin: An Observational Cohort Study

Risk of acute kidney injury and survival in patients treated with Metformin: an observational cohort study 1Renal Unit, Ninewells Hospital, Dundee, DD1 9SY UK 2Division of Population Health Sciences, School of Medicine, University of Dundee, Dundee, UK 3Institute of Genetics and Molecular Medicine University of Edinburgh, Edinburgh, UK 4Division of Molecular & Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK 5Department of Medicine, University of Dundee, Dundee, UK 6Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK 7Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, UK 8Department of Medicine, Western General Hospital, Edinburgh, UK Samira Bell, Phone: 00 44 1382 660111, Email: [email protected] . Received 2017 Feb 17; Accepted 2017 May 11. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated. This article has been cited by other articles in PMC. Whether metformin precipitates lactic acidosis in patients with chronic kidney disease (CKD) remains under debate. We examined whether metformin use was associated with an increased risk of acute kidney injury (AKI) as a proxy for lactic acidosis and whether survival among those with AKI varied by metformin exposure. All individuals with type 2 diabetes Continue reading >>

Acute Renal Failure And Severe Lactic Acidosis Due To Metformin

Acute Renal Failure And Severe Lactic Acidosis Due To Metformin

Metformin may rarely cause lactic acidosis in patients with predisposing factors of acidosis or tissue hypoxia, like acute renal or heart failure, liver failure, dehydration, alcohol consumption or serious infection. Mortality may approach 50% in these cases. A 70-year-old lady came to the emergency unit because of vomits and diffuse abdominal pain. Five days ago, she had visited our hospital for the same reason, with normal findings on physical and laboratory examination. Her medical history included diabetes mellitus under metformin/vildagliptin and dementia. The patient was confused and disoriented, afebrile, oliguric, with tachypnea and diffuse abdominal tenderness. Pressure was 130/70mmHg. Blood gases revealed severe lactic acidosis (lactate>15mmol/L), pH=6.84, PCO2=7mmHg, pO2=133mmHg, glucose=57mg/dL, HCO3<3mmol/L. Abnormal laboratory tests included creatinine=5.3mg/dL, urea=152mg/dL, WBC=17000/L, hemoglobin=12.3gr/dL, sodium=133mmol/L, potassium=4.4mmol/L, ESR=43mm/h. Chest x-ray, abdominal ultrasound (to exclude obstructive nephropathy) and echocardiography were normal. The patient received 400mL bicarbonate 4.8%, aggressive hydration, dopamine (diuretic dose) and 160mg furosemide. Because of clinical deterioration she underwent hemodialysis. She was treated, according to guidelines, as for severe sepsis with meropenem. Blood and urine cultures were negative. On 1st day, ECG showed ischemic lesions, which resolved with nitrates. Abdominal CT was normal. She remained afebrile after the 1st day (low grade fever). Overall, the patient underwent three hemodialysis sessions (resistant severe lactic acidosis, low bicarbonates). On 2nd day, she was well oriented. She was discharged 8 days later with urea=59mg/dL and creatinine=1.6mg/dL. After 20 days, creatinine was 1 Continue reading >>

A Case Of Metformin-induced Acute Kidney Injury Without Lactic Acidosis: A Case Report

A Case Of Metformin-induced Acute Kidney Injury Without Lactic Acidosis: A Case Report

A Case of Metformin-Induced Acute Kidney Injury without Lactic Acidosis: A Case Report *** A Case of Metformin-Induced Acute Kidney Injury without Lactic Acidosis: A Case Report 1Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea. [email protected] 2Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea. Metformin is an oral antidiabetic drug in the biguanide class, which is used for type 2 diabetes. The side effects of metformin are mostly limited to digestive tract symptoms, such as diarrhea, flatulence and abdominal discomfort. The most serious potential adverse effect of metformin is lactic acidosis. A 51-year-old man was admitted due to hypoglycemia as a result of an overdose of antidiabetic drugs. He took massive dose of metformin. Conservative treatment failed for metabolic acidosis without lactic acidosis accompanied by acute kidney injury. Hemodialysis was executed to correct the high anion gap metabolic acidosis and acute kidney injury, and the patient recovered fully from metabolic acidosis. This case illustrates that the presence of clinical conditions, such as metformin-induced acute kidney injury and metabolic acidosis, can be developed without lactic acidosis. Prompt recognition of metabolic acidosis and early intervention with hemodialysis can result in a successful clinical outcome. Continue reading >>

Diabetes Drug Metformin Safe For Patients With Kidney Disease: Review

Diabetes Drug Metformin Safe For Patients With Kidney Disease: Review

TUESDAY, Dec. 23, 2014 (HealthDay News) -- Although metformin, the popular type 2 diabetes medication, is usually not prescribed for people with kidney disease, a new analysis shows the drug may be safer for these patients than once thought. Metformin has been used in the United States for two decades to help lower blood sugar levels among people with type 2 diabetes. The U.S. Food and Drug Administration cautions that people with kidney disease should not take the drug because it could increase their risk for a potentially serious condition called lactic acidosis. This is when lactic acid builds up in the bloodstream after oxygen levels in the body are depleted. After reviewing published research to evaluate the risks associated with metformin among people with mild to moderate kidney disease, a team of researchers led by Dr. Silvio Inzucchi, a professor of medicine at Yale University, found these patients were at no greater risk for lactic acidosis than people who were not taking the drug. "What we found is that there is essentially zero evidence that this is risky," Inzucchi, who is also medical director of the Yale Diabetes Center, said in a university news release. "The drug could be used safely, so long as kidney function is stable and not severely impaired," he said. Despite warnings, many doctors are already prescribing metformin to patients with kidney disease, the study published in the Dec. 24/31 issue of the Journal of the American Medical Association revealed. "Many in the field know that metformin can be used cautiously in patients who have mild to moderate kidney problems," Inzucchi said. "Most specialists do this all the time." Still, the researchers said their findings are significant because many doctors stop prescribing metformin once their patients g Continue reading >>

Metformin Lactic Acidosis, Acute Renal Failure And Rofecoxib

Metformin Lactic Acidosis, Acute Renal Failure And Rofecoxib

Accepted for publication: July 9, 2003 Drug‐related causes of morbidity and mortality are recognized increasingly.1 In recent years, a new class of non‐steroidal anti‐inflammatory drug (NSAIDS), the COX 2 inhibitors, have been developed. They reduce the incidence of gastrointestinal side effects compared with traditional NSAIDs.2 This benefit has made these drugs increasingly attractive, but it should be remembered that this benefit does not extend to the renal system. The following describes a patient with acute renal failure and lactic acidosis as a result of concurrent treatment with metformin. Rofecoxib may have been a precipitating factor. Case report A 58‐yr‐old female presented with a 4‐day history of increasing lethargy, anorexia, abdominal pain, and nausea. Her abdominal pain and nausea became worse on the fifth day and her family sought medical help when her conscious level began to become impaired. Her medical history included 10 years of type 2 diabetes mellitus treated with diet modification and metformin 500 mg bd, and mild osteoarthritis of the knees. On arrival at the Accident and Emergency department she was severely agitated (GCS E3V3M4), ventilatory frequency 45, arterial pressure 130/70 mm Hg, heart rate 110 beats min–1, peripheral oxygen saturation 95% on air and blood sugar 6.2 mmol litre–1. Physical examination was unreliable because of patient agitation but abdominal palpation revealed a tender abdomen. Arterial blood gases were: pH 6.8, PaCO2 2.6 kPa, Po2 10.2 kPa, plasma bicarbonate 5 mmol litre–1, base deficit 27.4 mmol litre–1, and plasma lactate 19.8 mmol litre–1. Her biochemical profile revealed a sodium of 140 mmol litre–1, potassium 4.4 mmol litre–1, urea 27.4 mmol litre–1 and creatinine 796 mmol litre–1. In Continue reading >>

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