Vitamin B12 Deficiency In Metformin-treated Type-2 Diabetes Patients, Prevalence And Association With Peripheral Neuropathy
The association between long-term metformin use and low vitamin B12 levels has been proven. However, the prevalence estimates of metformin-induced vitamin B12 deficiency showed considerable variation among the studies. The potential of the deficiency to cause or worsen peripheral neuropathy in type-2 diabetes mellitus (T2DM) patients has been investigated with conflicting results. The aim of the study was to investigate: 1) the prevalence of vitamin B12 deficiency in T2DM patients on metformin; 2) the association between vitamin B12 and peripheral neuropathy; 3) and the risk factors for vitamin B12 deficiency in these patients. In this cross-sectional study, consecutive metformin-treated T2DM patients attending diabetes clinics of two public hospitals in South Africa were approached for participation. Participation included measuring vitamin B12 levels and assessing peripheral neuropathy using Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire. The prevalence of vitamin B12 deficiency (defined by concentrations <150 pmol/L) was determined. Those with NTSS-6 scores >6 were considered to have peripheral neuropathy. The relationship between vitamin B12 and peripheral neuropathy was investigated when the two variables were in the binary and continuous forms. Multiple logistic regression was used to determine risk factors for vitamin B12 deficiency. Among 121 participants, the prevalence of vitamin B12 deficiency was 28.1%. There was no difference in presence of neuropathy between those with normal and deficient vitamin levels (36.8% vs. 32.3%, P = 0.209). Vitamin B12 levels and NTSS-6 scores were not correlated (Spearmans rho =0.056, P = 0.54). HbA1c (mmol/mol) (OR = 0.97, 95% CI: 0.95 to 0.99, P = 0.003) and black race (OR = 0.34, 95% CI: 0.13 to 0.92, P = 0.033) wer Continue reading >>
Metformin Toxicity
Summarized from DellAglio D, Perino L, Kazzi Z et al. Acute metformin overdose: Examining serum pH lactate Levels and metformin concentrations in survivors versus nonsurvivors: A systematic review of the literature. Annals of Emerg Med 2009; 54: 818-23 Metformin, a blood-glucose-lowering drug widely used for treatment of type 2 diabetes, is associated with risk of potentially fatal metabolic (lactic) acidosis. This can occur not only following overdose but also at therapeutic dose in patients with pre-existing renal or liver disease. Results of arterial blood gas analysis reflect metabolic acidosis (reduced blood pH, reduced bicarbonate compensatory increase in pCO2) and increased plasma lactate. Is it possible, as might be intuitively expected, to predict survival in such cases from the severity of the acidosis and/or severity of the hyperlactatemia? That is the question addressed by a recent study. Investigators conducted a systematic review of the literature and identified 22 well-documented case histories of metformin overdose, five of which had a fatal outcome. For each of these cases, investigators abstracted lowest (nadir) pH, highest (peak) plasma lactate concentration and highest (peak) plasma metformin concentration. The median nadir pH among non-survivors was 6.71 (interquartile IQ range 6.71-6.73), this compared with median pH 7.30 (IQ range 7.22-7.36) for survivors. The median peak plasma lactate among non-survivors was 35 mmol/L (IQ range 33.3-39.0) and among survivors 10.8 mmol/L (IQ range 4.2-12.9). Results allowed the conclusion that patients who died following metformin overdose had much lower nadir blood pH and much higher peak plasma lactate concentration than those who survived. No patients with pH > 6.9 and plasma lactate < 25 mmol/L died. Intuiti Continue reading >>
Toxicity And Toxicokinetics Of Metformin In Rats
Advanced HF (heart failure) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. The antihyperglycaemic drug MET (metformin) affects substrate metabolism, and its use might be associated with improved outcome in diabetic HF. The aim of the present study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Volume-overload HF was induced in male Wistar rats by creating ACF (aortocaval fistula). Animals were randomized to placebo/MET (300 mgkg(-1) of body weightday(-1), 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (week 21). A separate cohort served for survival analysis (n=10-90/group). The ACF group had marked cardiac hypertrophy, increased LVEDP (left ventricular end-diastolic pressure) and lung weight confirming decompensated HF, increased circulating NEFAs (non-esterified 'free' fatty acids), intra-abdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triacylglycerol (triglyceride) content and attenuated myocardial (14)C-glucose and (14)C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum NEFAs, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK (AMP-activated protein kinase) signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival, despite reaching therapeutic serum levels (2.20.7 g/ml). In conclusion, MET-induced enhancement of myocardial fatty acid oxidation had a neutral effect on ca Continue reading >>
Toxicity And Toxicokinetics Of Metformin In Rats
Volume 243, Issue 3 , 15 March 2010, Pages 340-347 Toxicity and toxicokinetics of metformin in rats Get rights and content Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200mg/kg/day by oral gavage for 13weeks. Administration of 900mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200mg/kg/day, body weight loss and clinical signs in rats given 600mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses 600mg/kg/day. There were no significant sex differences in mean AUC024 or Cmax nor were there significant differences in mean AUC024 or Cmax following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200mg/kg/day (mean AUC024=41.1g h/mL; mean Cmax=10.3g/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations. Continue reading >>
Metformin Overdosage
Metformin is a biguanide used to treat type 2 diabetes mellitus and most commonly prescribed oral hypoglycemic agent. Metformin is now also used to treat polycystic ovary syndrome and some malignancies. Despite a good safety profile in a majority of patients with diabetes, the risk of metformin-associated lactic acidosis is genuine when safety guidelines are ignored. Overdoses with metformin are rare, but may result in serious consequences. Case reports and small case series of serious toxicity from metformin overdosage can be found in the medical literature, often with the portrayal of extracorporeal methods for the management of the subsequent severe lactic acidosis. Lactic acidosis can defined as a metabolic acidosis with a blood pH less than 7.35 and a serum lactate more than 2 mmol per liter. It can occur either with therapeutic metformin dosing (which is rare) or in overdose situations. 0.03 cases of lactic acidosis per 1000 patient-years occur within therapeutic dosing, with a majority of these cases among patients that have contraindications to metformin (such as renal insufficiency). In overdose situations, lactic acidosis is seen much more habitually, even though the precise incidence is unclear. Lactic acidosis has been observed in 1.6% of metformin exposures reported to poison control centers; nevertheless, merely 10% of these exposures were due to deliberate overdoses. The incidence of metformin-associated lactic acidosis was 12.8% in a review of poison control center inquiries from Germany. The minimum reported lethal dose was found in a 42 year-old patient who had a blood metformin level of 188 µg/ml (e.g. therapeutic range level is usually between 0.5–2.5 µg/ml). Although the intake of 35 g of metformin has shown to be lethal, the maximum reported to Continue reading >>
Metformin Litfl Life In The Fast Lane Medical Blog
Metformin rarely causes hypoglycaemia but it can cause a profound lactic acidosis in overdose and in patients with renal failure. Used therapeutically to inhibit glucogenogenesis and stimulate peripheral glucose uptake, in toxic doses it causes a profound lactaemia. All the mechanisms are unclear but it is in part due to the inhibition of gluconeogenesis (which lactate is required). Therefore in healthy individuals there is some build up of lactate, this is normally excreted in the urine but at impaired renal function or an acute overdose there is excess lactate. It is not metabolised and excretion relies solely on renal excretion A lactic acidosis in the context of therapeutic metformin has a high mortality rate and an underlying cause (sepsis) needs to be managed Metformin overdose is usually benign but doses > 10 grams are concerning Lactic acidosis will occur in these individuals who are susceptible (renal, cardiac, respiratory failure) or in patients who have ingested co-ingestants or are on medications that impair cardiac and renal function Severe lactic acidosis usually manifests with non-specific symptoms several hours later but can progress to coma, shock and death Children: Unintentional ingestion of up to 1700mg is benign. Hypoglycaemia, if present can be managed with dextrose . Severe acidosis and hyperkalaemia may require the administration of sodium bicarbonate (1 2 mmol/kg). However, it is likely the patient is already hyperventilating to compensate for the metabolic acidosis, haemodialysis is the ultimate priority. If in a patient on therapeutic metformin, stop further administration and seek the underlying cause for their deterioration (sepsis, acute kidney injury) Screening: 12 lead ECG, BSL, Paracetamol level 50 grams of charcoal to the co-operative Continue reading >>
Severe Acidosis, Renal Failure And Metformin Toxicity
Severe Acidosis, Renal Failure and Metformin Toxicity The call comes in just after midnight. A 67 year old male has been brought to the Emergency Department. He had complained of lower back pain, feeling unwell, with two episodes of vomiting. He arrived in the Emergency Department, aggitated, complaining of severe pain and having already been given, 370mcg of Fentanyl by the ambulance.His past history is of Hypertension and Diabetes and he takes Amlodipine and Metformin. His vitals were: T 30.9, HR 60, Resp Rate 36, BP 100/35, GCS E1,V2,M4 =7 A rapid clinical examination demonstrated, clear lungs, a soft abdomen and a FAST scan of the abdomen was normal. The patient was intubated usingKetamine and Rocuronium and a size 7.5 endotracheal tube was passed. The airway was a Cormach Lehane grade 4. 100mmol of NaHCO3 was given intravenously to treat the low pH. A CT scan of the chest and abdomen was performed, looking for a cause for the patients back pain and high lactate ie., was there an ischaemic bowel, or a large aorta. The findings were some dependent atelectasis in the lungs and one atrophic kidney. Due to the atelectasis on CT, Ceftriaxone was given initially with anantivirals. Pip-tazidine was added iven that sepsis was the concern in this patient (even though he was not febrile) pip-tazidine was added. The patients Blood Pressure became somewhat volatile via a Non- Invasive Cuff and so an arterial line was inserted, reading a systolic BP of 80mmHg. Peripheral Metaraminol was used in 1mg boluses, to maintain blood pressure and a Metaraminol infusion was commenced. A further set of gases was taken without much improvement in acidosis. During this time the patients blood pressure continued to drop. A noradrenaline infusion was commenced. With very little improvement in Continue reading >>
Toxicology Of Oral Antidiabetic Medications
Toxicology of Oral Antidiabetic Medications Am J Health Syst Pharm.2006;63(10):929-938. In 1996, the Food and Drug Administration approved the labeling for metformin (dimethylbiguanide), the only biguanide currently available in the United States. Phenformin, the other previously available biguanide, was withdrawn from the market in 1977 because of an association with lactic acidosis. Buformin, another biguanide, is not available in the United States. The complex of mechanisms of action of metformin is multifaceted but appears to include delayed glucose absorption, increased intestinal glucose utilization, increased intestinal lactate production, inhibition of hepatic gluconeogenesis, decreased lipid oxidation, decreased free fatty acid concentration, and increased peripheral insulin-related glucose uptake.[ 70 ] Metformin absorption is incomplete, with 20-30% found in the feces. Oral bioavailability is 40-60%, depending on the dose ingested, with greater doses producing lower bioavailability.[ 71 ] The reduced bioavailability may result from the drug binding by the intestinal wall.[ 72 ] The rate of absorption is slower than the rate of elimination, which makes absorption a rate-limiting step in the elimination half-life.[ 73 , 74 ] Absorption, in therapeutic doses, is expected to be complete in 6 hours. In an overdose situation involving massive doses, absorption may be prolonged. About 90% of the absorbed metformin is eliminated through the kidneys within the first 24 hours in patients with normal renal function.[ 72 ] Metformin has no metabolites. Metformin is the second most commonly prescribed oral antidiabetic medication in both monotherapy and combination therapy.[ 11 ] In 2004, metformin had the highest number of reports to U.S. poison control centers and the Continue reading >>
Metformin - National Library Of Medicine Hsdb Database
For more information, search the NLM HSDB database. IDENTIFICATION AND USE: Metformin is antihyperglycemic, not hypoglycemic agent. It does not cause insulin release from the pancreas and does not cause hypoglycemia, even in large doses. HUMAN EXPOSURE AND TOXICITY: Metformin is believed to work by inhibiting hepatic glucose production and increasing the sensitivity of peripheral tissue to insulin. It does not stimulate insulin secretion, which explains the absence of hypoglycemia. Metformin also has beneficial effects on the plasma lipid concentrations and promotes weight loss. Accumulation of metformin may occur in patients with renal impairment, and such accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic disease. Lactic acidosis constitutes a medical emergency requiring immediate hospitalization and treatment; lactic acidosis is characterized by elevated blood lactate concentrations, decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. Lactic acidosis also may occur in association with a variety of pathophysiologic conditions, including diabetes mellitus, and whenever substantial tissue hypoperfusion and hypoxemia exist. Approximately 50% of cases of metformin-associated lactic acidosis have been reported to be fatal. No evidence of mutagenicity or chromosomal damage was observed in in vitro test systems, including human lymphocytes assay. ANIMAL STUDIES: No evidence of carcinogenic potential was seen in a 104-week study in male and female rats receiving metformin hydrochloride dosages up to and including 900 mg/kg daily or in a 91-week study in male and female mice receiving metformin hydrochloride at dosages up to and including 1500 mg/kg daily. Cancer preventive e Continue reading >>
Metformin Scavenges Methylglyoxal To Form A Novel Imidazolinone Metabolite In Humans
Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, Department of Chemical & Environmental Engineering, Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States *E-mail: [emailprotected] . Tel: (313) 577-1574. Fax: (313) 577-0457. Cite this: Chem. Res. Toxicol. 2016, 29, 2, 227-234 Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Methylglyoxal (MG) is a highly reactive dicarbonyl compound involved in the formation of advanced glycation endproducts (AGE). Levels of MG are elevated in patients with type-2 diabetes mellitus (T2DM), and AGE have been implicated in the progression of diabetic complications. The antihyperglycemic drug metformin (MF) has been suggested to be a scavenger of MG. The present work examined and characterized unequivocally the resulting scavenged product from the metforminMG reaction. The primary product was characterized by 1H, 13C, 2D-HSQC, and HMBC NMR and tan Continue reading >>
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Fatal Metformin Intoxication With Markedly Elevated Blood And Liver Concentrations
Fatal Metformin Intoxication with Markedly Elevated Blood and Liver Concentrations California Poison Control System, San Diego Division and Clinical Pharmacy, University of California San Francisco School of Pharmacy, 200 W. Arbor Dr., San Diego, CA 92103 Author to whom correspondence should be addressed. Email: [email protected] . Search for other works by this author on: San Diego County Medical Examiner's OfficeToxicology, 5555 Overland Ave., Suite 1411, San Diego, CA 92123 Search for other works by this author on: San Diego County Medical Examiner's OfficeToxicology, 5555 Overland Ave., Suite 1411, San Diego, CA 92123 Search for other works by this author on: San Diego County Medical Examiner's OfficeToxicology, 5555 Overland Ave., Suite 1411, San Diego, CA 92123 Search for other works by this author on: Journal of Analytical Toxicology, Volume 36, Issue 9, 1 November 2012, Pages 657659, F. Lee Cantrell, Craig L. Nelson, Ray D. Gary, Iain M. McIntyre; Fatal Metformin Intoxication with Markedly Elevated Blood and Liver Concentrations, Journal of Analytical Toxicology, Volume 36, Issue 9, 1 November 2012, Pages 657659, The highest postmortem metformin concentrations are recorded utilizing a sensitive and specific analytical procedure. The peripheral blood metformin concentration was 240 mg/L, the liver concentration was 240 mg/kg and the gastric concentration was 1,700 mg. Additionally, an antemortem blood sample collected shortly after admission revealed a metformin concentration of 210 mg/L. These data, revealing a liver to peripheral blood ratio of 1.0, provide additional support that metformin is not subject to postmortem redistribution. Intentional self-poisonings with metformin can result in death, despite multiple medical interventions. Since being appro Continue reading >>
Hyperlactataemia And Clinical Severity Of Acute Metformin Overdose
Hyperlactataemia and clinical severity of acute metformin overdose Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia Funding: G. K. Isbister is supported by an NHMRC Senior Research Fellowship ID1061041. Please review our Terms and Conditions of Use and check box below to share full-text version of article. I have read and accept the Wiley Online Library Terms and Conditions of Use. Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. Get access to the full version of this article. View access options below. You previously purchased this article through ReadCube. View access options below. Logged in as READCUBE_USER. Log out of ReadCube . Although metforminassociated lactic acidosis is well described, there is less information on metformin overdose and whether it is of similar severity. This study aims to describe the clinical features, laboratory investigations and outcome of acute metformin overdoses. Retrospective case series of acute metformin overdoses (>3 g) admitted to a toxicology unit over 20 years. Cases were identified from a prospective database and data extracted included demographics, dose, coingestants, clinical effects, investigations, treatment and outcomes. There were 36 acute metformin overdose cases. Median age 41 years old (1568 years old); 25 were female. Median ingested dose was 10 g (interquartile range (IQR): 516. Continue reading >>
6 Pearls About Metformin And Lactic Acidosis
Metformin accumulation: Lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Vecchio S et al. Clin Toxicol 2014 Feb;52:129-135. Metformin is frequently used alone or in combination to treat type 2 diabetes. It lowers blood glucose by decreasing hepatic gluconeogenesis, predominantly by inhibiting mitochondrial respiratory chain complex I. The drug is eliminated mainly by the kidneys, and acute or chronic renal insufficiency may allow accumulation of the drug with increasing levels. A small percentage of patients on metformin develop severe lactic acidosis. There has been an ongoing controversy as whether this acidosis is metformin-associated or metformin-induced. This paper, from the Pavia Poison Control Centre in Northern Italy, helps shed light on this question. The authors retrospectively reviewed patients admitted to their toxicology unit over a 5-year period. Eligible patients were on chronic metformin therapy at the time of admission, had lactic acidosis (pH < 7.35, arterial lactate > 5 mmol/L), and elevated metformin levels (plasma metformin > 4 mcg/ml). Cases of acute overdose were excluded. The study objective was to correlate the metformin levels with measured pH, lactate levels, renal function, and mortality rate. Sixty-six eligible patients were identified. All patients presented with acute renal failure and severe lactic acidosis (mean pH 6.91, mean lactate 14.36 mmol/L). About half the patients had a pre-existing contraindication to metformin therapy, predominantly renal failure and/or heart disease. Approximately 75% presented after several days of a mild gastrointestinal prodrome with nausea, vomiting, and diarrhea; this may either have represented the initial manifestations of metformin po Continue reading >>
Survival Following A Metformin Overdose Of 63 G: A Case Report
Survival Following a Metformin Overdose of 63 g: A Case Report Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus Amtssygehus, DK8000 Aarhus C, Denmark Author for correspondence: Jrgen Rungby, Department of Endocrinology C, Aarhus University Hospital, Tage Hansensgade, DK8000 Aarhus C, Denmark (fax +45 8949 7659, Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus Amtssygehus, DK8000 Aarhus C, Denmark Author for correspondence: Jrgen Rungby, Department of Endocrinology C, Aarhus University Hospital, Tage Hansensgade, DK8000 Aarhus C, Denmark (fax +45 8949 7659, Please review our Terms and Conditions of Use and check box below to share full-text version of article. I have read and accept the Wiley Online Library Terms and Conditions of Use. Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. Metformin is a biguanide used in the treatment of type 2 diabetes mellitus. It lowers hepatic glucose production and peripheral insulin resistance. Hypoglycaemia is seen only after intake of toxic doses or in combination with other antidiabetic drugs or after prolonged fasting. As metformin is excreted by the kidneys, care must be taken in renal insufficiency or liver disease because of risk of lactic acidosis. Large overdoses of metformin can lead to lactic acidosis as well. Suicide with metformin is rare. Intake of 35 g of metformin has been shown to be lethal ( Teale et al. 1998 ). In the present paper we report on the treatment and outcome of a 70 year old man after ingestion of 63 g of metformin. Previously, survival after intake of up to 50 g has been described. A 70 year old man with type 2 diabetes mellitus who was being treated with metformin 850 mg twice daily and glimepiride Continue reading >>
A Reappraisal On Metformin
Author links open overlay panel TubaAdaka AfshinSamadib Aye Zeynepnala SunaSabuncuolua The mechanisms and pharmacokinetic properties, genetic variants of transporters, side effects of metformin is reevaluated. An update on potential clinical benefits of metformin in terms of aforementioned major diseases is proposed. In the review possible mechanism of MET against cancer in non-diabetics is proposed. This review investigates the different biological effect of Metformin (MET) in different conditions. MET is an oral antidiabetic drug used for the treatment of type 2 diabetes mellitus (T2DM) particularly in overweight people. The main mechanism of action of the MET is inhibition of hepatic glucose production and reduction of insulin resistance. In addition to its antidiabetic effects, MET is also found to be related with the risk for development of several human solid cancers types such as colorectal, breast and pancreas cancer in the diabetic patients. Nowadays according to some researches, MET is believed to decrease or prevent aging and mortality. Moreover, clinical and experimental evidence has shown that MET has beneficial effects in patient with obesity, polycystic ovarian syndrome and Alzheimer's disease. Recent studies have shown that activation of adenosine monophosphate-activated protein kinase (AMPK) by MET can explain its beneficial metabolic effects. In this manuscript, a reevaluation of mechanisms as well as pharmacokinetic properties, genetic variants of transporters, drug-drug interactions, side effects and potential clinical benefits of MET have been reviewed. Continue reading >>
