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Metformin Toxicology

Toxicology Brief: Metformin Overdose In Dogs And Cats

Toxicology Brief: Metformin Overdose In Dogs And Cats

Unlike the sulfonylurea medications (e.g. glyburide or glipizide), metformin does not increase pancreatic insulin secretion and, thus, even in overdose situations, does not cause substantial hypoglycemia. In people, acute ingestions of up to 85 g1,133 mg/kg for the average 165-lb (75-kg) persondid not result in hypoglycemia.11 However, in individuals with pre-existing malnutrition, with a history of excessive exercise coupled with inadequate food intake, or taking other glucose-lowering drugs concurrently, hypoglycemia may occur.1,8 While life-threatening lactic acidosis was a frequent adverse effect in people taking phenformin, an association between lactic acidosis and metformin used therapeutically or in cases of acute overdoses is rare. Lactic acidosis is usually associated with long-term use,6 and once it develops, it has been associated with a 50% to 75% mortality rate.4 Lactic acidosis in people receiving metformin has occurred primarily in diabetic patients with significant renal insufficiency. Additionally, patients with congestive heart failure who require pharmacologic management for hypoperfusion and hypoxemia are at increased risk of lactic acidosis. The threat of lactic acidosis increases with the extent of renal dysfunction and the patient's age.9 These conditions can result in decreased renal clearance of the drug, and, consequently, lactic acidosis can occur. The postulated mechanism is that metformin causes decreased hepatic production of glucose from lactate (via the Cori cycle). The net result is decreased conversion of lactate to glucose and subsequent lactic acidosis.2,8,9 No minimum toxic metformin dose for the development of lactic acidosis is established in people. In one case report, a 15-year-old healthy girl ingested 38.25 g (550 mg/kg) of m Continue reading >>

Hyperglycemia After Metformin Overdose: A Case Report Sabiha Sahina, D, Cigdem Binayb, Enver Simsekb, Ener Cagri Dinleyicia,

Hyperglycemia After Metformin Overdose: A Case Report Sabiha Sahina, D, Cigdem Binayb, Enver Simsekb, Ener Cagri Dinleyicia,

Articles © The authors | Journal compilation © Int J Clin Pediatr and Elmer Press Inc™ | www.theijcp.org This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited 44 Case Report Int J Clin Pediatr. 2016;5(3-4):44-46 ressElmer Kursat Bora Carmanc Abstract We present a case of a 16-year-old non-diabetic girl who ingested over 35 tablets (glucophage Merck 850 mg) of metformin in a sui- cide attempt. She presented to pediatric emergency department with severe lactic acidosis and a progressively increasing serum glucose level. She was in a coma state at the time of admission, Glasgow coma scale was 3/15 and arterial blood pressure was 106/45 mm Hg. Arterial blood gas (ABG) analysis indicated severe metabolic acido- sis (pH 6.7) with high anion gap -30.5, PCO2 13.2, HCO3 3.9, BE -30, lactate 14.54 mmol/L, blood glucose 497, amylase 531 IU/L, and uric acid 10.47 mg/dL. Serum ethanol, acetaminophen and salicylates were measured and found to be undetectable. Electrocardiographic monitoring demonstrated a narrow-complex sinus tachycardia. She was intubated, totally 2,000 cc/m2 fluid and NaHCO3 were given, and insulin infusion 0.1 units/kg was started for blood glucose of 497 mg/dL. But the patient suffered several cardiac arrests with pulse- less electrical activity and ultimately expired 25 h after the ingestion. The patient was transferred to pediatric intensive care unit (PICU) for high-volume continuous veno-venous hemofiltration (CVVH). Despite the supportive care in ICU, she died due to multiple organ failures after 48 h of hospitalization. Keywords: Continue reading >>

Fatal Metformin Intoxication With Markedly Elevated Blood And Liver Concentrations

Fatal Metformin Intoxication With Markedly Elevated Blood And Liver Concentrations

Since being approved by the United States Food and Drug Administration in 1995, metformin, a member of the biguanide class of oral hypoglycemics, has become one of the most popular medications prescribed in the United States (1). Because of its widespread use, it is not surprising that over 7,500 cases of metformin exposures were reported to United States poison control centers in 2010 (2). Despite this large number of exposures, only five reported fatalities occurred where metformin was detected during postmortem analysis. Upon reviewing the literature, the highest reported postmortem metformin concentrations in central blood and the liver are 77.3 mg/L (3) and 146 mg/kg (4), respectively. This study reports the highest peripheral blood and liver metformin concentrations on record. The decedent was a 57-year-old woman who had a medical history of hypertension, hypercholesterolemia, diabetes mellitus, depression and anxiety. Her regular medications included mirtazapine, atorvastatin, metformin, glipizide, pioglitazone/glimepiride, trazodone, losartan, clonazepam, ubidecarenone, aspirin and vitamins. One evening while visiting relatives, the decedent developed persistent vomiting and diarrhea. When questioned, she admitted to ingesting some of her medication with drain cleaner. Emergency medical services were immediately contacted and the patient was transported to a hospital by paramedics. Upon arrival, she complained of oral irritation, but refused to give further information to staff. Initial vital signs were: blood pressure, 116/85 mm/Hg; heart rate, 120 beats per min; respiratory rate, 19; temperature, 99.0°F; oxygen saturation, 99% on room air. An admission urine toxicology screen was negative for opiates, methadone, barbiturates, phencyclidine, amphetamines, benz Continue reading >>

Metformin Toxicity

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 >>

Ph 6.68surviving Severe Metformin Intoxication

Ph 6.68surviving Severe Metformin Intoxication

Metformin, a widely used anti-diabetic agent of the biguanide family, although generally safe, 1 , 2 , 3 , 4 holds the risk of developing a potentially lethal acidosis. 5 , 6 The association between lactic acidosis and metformin is well-established but rarely seen in patients taking this medication. 7 Its elimination relies solely on kidneys excretion, 8 so its accumulation is feasible in just two circumstances: renal failure (RF) and acute overdosage. At normal dosage, a toxic accumulation of drug requires time after the development of RF, due to metformin high clearance. About 90% of the drug is eliminated by glomerular filtration and tubular secretion (serum half-life of 1.55 h). Moreover, RF is itself associated with acidosis as it impairs kidneys ability to excrete protons. Acute intoxication on the other hand is a viable option in those cases where renal function is normal and can correlate with a psychiatric disorder. The mechanism thought to be responsible for lactic acidosis is suppression of gluconeogenesis forming lactate, pyruvate, glycerol and amino acids leading to lactate accumulation, 9 a risk that is increased by either chronic or acute RF (ARF). Usually hyperlactatemia is the most common finding leaving lactic acidosis for the most severe intoxications. A 47-year-old, apparently previously fit, non-insulin-dependent diabetic male was brought to the Emergency Department for hypoglycemia, agitation and hyperventilation. Ambulance crew found blood glucose level at 1.33 mmol/l (24 mg/dl) and administered 20 ml of 33% glucose solution followed by other 250 ml at 5%. At the arrival in the Emergency Room, the patient was confused and agitated with no signs of respiratory distress or shock. Arterial blood gases (ABG) and laboratory tests are summarized in Tab Continue reading >>

Severe Acidosis, Renal Failure And Metformin Toxicity

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 >>

Metformin-associated Lactic Acidosis Following Intentional Overdose Successfully Treated With Tris-hydroxymethyl Aminomethane And Renal Replacement Therapy

Metformin-associated Lactic Acidosis Following Intentional Overdose Successfully Treated With Tris-hydroxymethyl Aminomethane And Renal Replacement Therapy

Metformin-Associated Lactic Acidosis following Intentional Overdose Successfully Treated with Tris-Hydroxymethyl Aminomethane and Renal Replacement Therapy Ngan Lam ,1,2 Gurbir Sekhon ,3and Andrew A. House 1,3 1Division of Nephrology, Department of Medicine, Western University, London, ON, Canada N6A 3K7 2London Health Sciences Centre, Kidney Clinical Research Unit, Victoria Hospital, Westminster Tower 800 Commissioners Road East, London, ON, Canada N6A 4G5 3Department of Medicine, Western University, London, ON, Canada N6A 3K7 Received 19 February 2012; Accepted 6 May 2012 Academic Editors: Y.Fujigaki, D.Packham, A.Papagianni, and H.Schiffl Copyright 2012 Ngan Lam 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. A 43-year-old woman was brought to the hospital with severe metabolic acidosis (pH 6.56, bicarbonate 3 mmol/L, and lactate 18.4 mmol/L) and a serum creatinine of 162 mol/L with a serum potassium of 7.8 mmol/L. A delayed diagnosis of metformin-associated lactic acidosis was made, and she was treated with tris-hydroxymethyl aminomethane (THAM) and renal replacement therapy (RRT). Following a complete recovery, she admitted to ingesting 180 tablets (90 grams) of metformin. Her peak serum metformin concentration was 170 g/mL (therapeutic range 1-2 g/mL). Our case demonstrates an intentional metformin overdose resulting in lactic acidosis in a nondiabetic patient who was successfully treated with THAM and RRT. Metformin is an oral antihyperglycemic agent that is the first-line therapy for noninsulin-dependent diabetes mellitus [ 1 ]. Although the adverse event rate is 2030%, the majority of the Continue reading >>

Pharmacology And Toxicology: Treatment Of Poisons - Metformin Intoxication

Pharmacology And Toxicology: Treatment Of Poisons - Metformin Intoxication

Pharmacology and Toxicology: Treatment of Poisons - Metformin Intoxication Pharmacology and Toxicology: Treatment of Poisons - Metformin Intoxication Does this patient have metformin intoxication? Since its introduction to the US market in 1995, the biguinide, metformin has become one of the most prescribed oral hypoglycemics. It is now considered the first line agent to treat type 2 diabetes. Because of its similarity to the drug another biguinide, phenformin, there was concern that it might increase the risk of lactic acidosis as was seen in phenformin. This delayed its release in the United States and led to a number of safety studies in the 1990s. One such study compared the incidence of lactic acidosis in patients treated with metformin and found that among the 7,227 patients followed on metformin, there were no incidents of lactic acidosis reported. Following its introduction, there have been a number of comparative studies with other oral agents for diabetes showing that metformin has a superior safety profile and excellent efficacy. As per the manufacturer, metformin is contraindicated in patients with chronic kidney disease. This is defined as a creatinine 1.4 mg/dL in women and 1.5 mg/dL in men. There have been a number of studies in patients with diabetes and chronic kidney disease that show that metformin remains a very safe medication and a number of authors have argued that its use should no longer be restricted in chronic kidney disease. Other authors have argued that for consistency sake alone, metformin should be restricted by a creatinine clearance estimate as it is with most medications whose clearance depends on renal function rather than a serum creatinine. For the time being, this author recommends following the restricted use of metformin as desc Continue reading >>

Metformin Toxicity: A Report Of 204 Cases From Iran.

Metformin Toxicity: A Report Of 204 Cases From Iran.

Metformin Toxicity: A Report of 204 Cases from Iran. Author(s): Shahin Shadnia , Farnaz Barzi , Anvar Askari , Hossein Hassanian-Moghaddam , Nasim Zamani , Kimia Ebrahimian . Department of Clinical Toxicology, Loghman Hakim Hospital, Karegar Street, Tehran, Iran. Objective: The aim of this study was to evaluate the frequency of metformin-associated lactic acidosis in ourmetformin-intoxicated patients, the general approach for their management, and determine the frequency of hypoglycemiaand outcome in these patients. We also wanted to see if there was a significant difference in the course and outcome ofmetformin poisoning between our patients and those reported in the literature. Materials and Methods: Files of all patients diagnosed with metformin toxicity were retrospectively evaluated. A purposemadequestionnaire containing the patients demographic data, vital signs and lab tests on presentation, time ofdevelopment of hypoglycemia and metabolic acidosis (if any), treatment modalities performed for the patients and theirindications, and the patients outcomes was filled. The patients were evaluated in total and then assigned into two groupsof metformin alone (group 1) and multi-drug toxicity including metformin (group 2) and were compared. Results: A total of 204 patients were reviewed. Fifty-five (26.9%) were in group 1 and 149 (73.1%) were in group 2.Sixteen and 52 patients in groups 1 and 2 had acidosis. Dialysis was performed in only four patients, all of whombelonged to group 1 (P = 0.005). They were all dialyzed only once. Two patients (1%) died both of whom were in group2. Groups 1 and 2 were insignificantly different in all characteristics except for their aspartate transaminase and creatinephosphokinase. Almost 23% of the patients in group 1 had experienced hy Continue reading >>

Toxicology Brief: Metformin Overdose In Dogs And Cats

Toxicology Brief: Metformin Overdose In Dogs And Cats

Metformin is an antihyperglycemic prescription medication labeled for the treatment of noninsulin-dependent (type 2) diabetes mellitus in people. Metformin belongs to the biguanide group of oral antidiabetic agents and is the only biguanide currently available in the United States. Other biguanides, such as phenformin and buformin, were withdrawn from the U.S. market because of their higher risk of serious adverse effects (increased risk of lactic acidosis).1 Metformin has also been studied in cats as a potential treatment for diabetes mellitus.2,3 Most cases of metformin toxicosis reported to the ASPCA Animal Poison Control Center (APCC) involve dogs that have ingested their owners' medication. Metformin is available in single-ingredient preparations as well as in combination with other antidiabetic agents. Under the trade name Glucophage (Bristol-Myers Squibb) and in several generic formulations, metformin is available as tablets containing 500, 850, or 1,000 mg of metformin hydrochloride. Glucophage XR, the extended-release formulation, contains 500 or 750 mg of metformin hydrochloride. Two other metformin-only products available in the United States are Riomet (Ranbaxy Pharmaceuticals), a liquid oral formulation containing 500 mg/5 ml of metformin hydrochloride, and Fortamet (First Horizon Pharmaceutical) 500- or 1,000-mg extended-release tablets. MECHANISM OF ACTION AND PHARMACOKINETICS Biguanides are thought to lower postprandial glucose concentrations in diabetic patients by increasing glucose uptake and decreasing glucose production. Although the precise mechanisms by which metformin exerts its antihyperglycemic effects are not entirely certain, they are largely attributed to a reduction in hepatic gluconeogenesis, a decrease in intestinal glucose absorption, an Continue reading >>

Fatal Metformin Overdose Presenting With Progressive Hyperglycemia

Fatal Metformin Overdose Presenting With Progressive Hyperglycemia

Go to: CASE REPORT A 29-year-old man ingested metformin in a suicide attempt. The patient consumed the entire remaining contents of his father’s prescription metformin bottle that originally contained 100 tablets of 850 mg each. The father stated that the bottle had contained at least three-quarters of its original contents, putting the ingested dose between 64 and 85 grams. The patient also consumed ethanol, but denied any other co-ingestants. The parents discovered the overdose around 6:30 a.m., about 5 ½ hours post-ingestion, when the patient began complaining of vomiting, diarrhea, thirst, abdominal pain and bilateral leg pain. Paramedics were called, who found the patient to be agitated with a fingerstick glucose level of 180 mg/dL. The patient had a history of psychosis and depression, including prior suicide attempts by drug ingestion. He was not taking any prescribed medications, having discontinued olanzapine and sertraline several months earlier. The patient had no personal history of diabetes, despite the family history of type II diabetes in his father, who was taking no other anti-diabetic medications than metformin. The patient admitted to daily ethanol and tobacco use, but denied any current or past use of illicit drugs. He had no surgical history or known allergies. Vital signs on arrival to the Emergency Department (ED) were temperature of 35.2°C (rectal), pulse of 113 beats/min, blood pressure of 129/59 mmHg, respirations at 28 breaths/min with 100% saturation via pulse oximetry on room air. The patient was awake and oriented x4, but agitated and slightly confused (GCS=14). Pupils were equal and reactive at 4mm and the oral mucous membranes were dry. Other than tachycardia, the heart and lung exams were unremarkable. The abdomen was mildly tender t Continue reading >>

Toxicity And Toxicokinetics Of Metformin In Rats

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 >>

6 Pearls About Metformin And Lactic Acidosis

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 >>

Vitamin B12 Deficiency In Metformin-treated Type-2 Diabetes Patients, Prevalence And Association With Peripheral Neuropathy

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 Intoxication

Metformin Intoxication

Can we love Metformin? Need we to fear it? Or perhaps we must give it Machiavellis ultimate accolade, and love and fear the drug with equal weight? Why to love Metformin? It is endorsed in the US, UK and Europe as the initial drug treatment for adults with type 2 diabetes. It treats diabetes, does not cause weight gain, does not increase risk of hypoglycaemia, and might reduce heart attacks and strokes. One tablet costs about 0.20 ($0.29/0.26) and the drug has been widely used for upwards of 60 years. So, must the love be tempered by fear? Metformin inhibits the mitochondrial respiratory chain, driving anaerobic metabolism and increasing lactic acid production. The drug is excreted almost entirely unchanged in urine so reduced kidney function may lead to accumulation of both metformin and lactate and therefore, a metformin-associated lactic acidosis (MALA). Where ingestion of overdose doses of metformin is seen, acutely or intentionally, this may be termed metformin-induced lactic acidosis (MILA). Notoriously, a similar drug, Phenformin, was withdrawn in the late 1970s after catastrophic lactic acidosis occurred in patients. The fear of metformin has lingered ever since, despite the overall incidence of lactic acidosis in metformin users being somewhere between 3 and 10 cases per 100,000 patient years and generally indistinguishable from the base rate in diabetics. Admittedly, reliable data specifically in patients with CKD is hard to come by and UK and US recommendations are to review the dose and not start the drug at an eGFR <45ml/min and stop the drug at <30ml/min. If youve seen a case of MALA, it might have extinguished any love you had for metformin; mortality is 30-50%, serum lactate is often over 20mmol/l and pH can fall below 7. Those are frightening numbers. Continue reading >>

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