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Toxicology Case Of The Month: Oral Hypoglycaemic Overdose

Toxicology Case Of The Month: Oral Hypoglycaemic Overdose

Toxicology case of the month: oral hypoglycaemic overdose J Soderstrom, L Murray, M Little, Sir Charles Gairdner Hospital, Perth, WA, Australia L Murray, F F S Daly, M Little, University of Western Australia, Perth, WA, Australia L Murray, F F S Daly, M Little, New South Wales Poison Information Centre, New Children's Hospital, Westmead, NSW, Australia F F S Daly, Royal Perth Hospital, Perth, WA, Australia Copyright 2006 Emergency Medicine Journal. This article has been cited by other articles in PMC. A teenager ingests 375 mg of glipizide and 14.5 g of melformin intentionally in a small country town. She presents to the local medical facility with symptoms and signs of hypoglycaemia. Using a risk assessment based approach, the management of suiphonylurea and metformin overdose is discussed. Sulphonylurea overdose invariably results in profound hypoglycaemia that requires resuscitation with IV dextrose and the use of octreotide as an antidote. Metfonnin overdose rarely causes problems. Keywords: glipizide, hypoglycaemia, lactic acidosis, metformin, overdose This is the first in a series of cases presented by the Western Australian Toxicology Service. The cases are selected for their relevance to emergency medicine practice and emphasise the importance of risk assessment in formulating a coherent management plan for the acutely poisoned patient (boxes 1 and 2). These principles were discussed in depth in the introductory article for this series. 1 A 15 year old female presents to the hospital of a small remote town 2600 km north east of Perth. Some 4 h ago, following a family dispute, she ingested all of her diabetic father's medications. Her family are unable to account for 755 mg glipizide and 29500 mg metformin tablets. On arrival, she is vomiting and appears anxious Continue reading >>

Metformin

Metformin

Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes,[4][5] particularly in people who are overweight.[6] It is also used in the treatment of polycystic ovary syndrome.[4] Limited evidence suggests metformin may prevent the cardiovascular disease and cancer complications of diabetes.[7][8] It is not associated with weight gain.[8] It is taken by mouth.[4] Metformin is generally well tolerated.[9] Common side effects include diarrhea, nausea and abdominal pain.[4] It has a low risk of causing low blood sugar.[4] High blood lactic acid level is a concern if the medication is prescribed inappropriately and in overly large doses.[10] It should not be used in those with significant liver disease or kidney problems.[4] While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes.[4][11] Metformin is in the biguanide class.[4] It works by decreasing glucose production by the liver and increasing the insulin sensitivity of body tissues.[4] Metformin was discovered in 1922.[12] French physician Jean Sterne began study in humans in the 1950s.[12] It was introduced as a medication in France in 1957 and the United States in 1995.[4][13] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[14] Metformin is believed to be the most widely used medication for diabetes which is taken by mouth.[12] It is available as a generic medication.[4] The wholesale price in the developed world is between 0.21 and 5.55 USD per month as of 2014.[15] In the United States, it costs 5 to 25 USD per month.[4] Medical uses[edit] Metformin is primarily used for type 2 diabetes, but is increasingly be Continue reading >>

Toxicology Of Oral Antidiabetic Medications

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 Overdosage

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 >>

Oral Hypoglycemic Agent Toxicitytreatment & Management

Oral Hypoglycemic Agent Toxicitytreatment & Management

Oral Hypoglycemic Agent ToxicityTreatment & Management Author: David Tran, MD; Chief Editor: Timothy E Corden, MD more... The main goal in oral hypoglycemic agent exposure is supportive care, which includes airway, breathing, and circulation. Intravenous administration of glucose rapidly resolves the effects of hypoglycemia. Its onset is quicker than oral administration of sugar, and it is safer in patients with a depressed mental status who should not take anything by mouth for fear of aspiration. Glucagon is helpful and can be administered intravenously, intramuscularly, or subcutaneously. Glucagon is particularly useful in the intramuscular mode when intravenous access cannot be obtained immediately. Generally, all symptomatic patients who present with hypoglycemia need admission to the hospital in a monitored setting. Patients who remain asymptomatic and who do not develop hypoglycemia in the first 8-12 hours may be discharged safely home. However, the data from one study suggest that because accidental ingestion of sulfonylurea results in delayed and often prolonged hypoglycemia, admission for at least 16 hours is recommended, with frequent glucose monitoring. [ 17 ] At minimum, patients need intravenous access. If the patient is lethargic, then oxygen, continuous cardiac monitoring, and pulse oximeter are indicated. Until the patient totally regains normal mental status, do not administer anything by mouth. Administer intravenous glucose to all patients with hypoglycemic symptoms. Depending on the amount of the drug and its half-life, patients may require intravenous glucose administration for anywhere from several hours to several days. If patients do not respond to continuous glucose administration with supplemental boluses, then octreotide or diazoxide can be Continue reading >>

Metformin Overview

Metformin Overview

Metformin is a prescription medication used to treat type 2 diabetes. Metformin belongs to a group of drugs called biguanides, which work by helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. This medication comes in tablet, extended-release tablet, and liquid forms. It is taken up to 3 times daily, depending on which form you are taking. Swallow extended-release tablets whole. Common side effects of metformin include diarrhea, nausea, and upset stomach. Metformin is a prescription medication used to treat type 2 diabetes. This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information. Metformin may be found in some form under the following brand names: Serious side effects have been reported including: Lactic Acidosis. In rare cases, metformin can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This build-up can cause serious damage. Lactic acidosis caused by metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking metformin over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who develop it. It is also important for your liver to be working normally when you take metformin. Your liver helps remove lactic acid from your blood. Make sure you tell your doctor before you use metformin if you have kidney or liver problems. You should also stop using metformin and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treate 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 >>

1322: Prolonged Hemodialysis-an Antidote For Metformin Induced Lactic Acidosis

1322: Prolonged Hemodialysis-an Antidote For Metformin Induced Lactic Acidosis

Introduction: A 60 year old Hispanic man with Type 2 diabetes mellitus and on Metformin was brought to the Emergency Department with vomiting and diarrhea of two days duration. On physical examination, he was noted to be hypothermic, hypotensive and confused. Laboratory work-up revealed severe life threatening high anion gap metabolic acidosis,hyperlactatemia and markedly elevated creatinine of 9 mg/dl (normal 0.6-1.2 mg/dl) without prior laboratory data. Patient was intubated, vasopressor and sodium bicarbonate intravenous drips initiated and arrangement made for urgent hemodialysis based on a high index of suspicion for metformin poisoning. After 4 hours of hemodialysis, there was marked improvement in the laboratory parameters post hemodialysis. He was given another session of hemodialysis with the same hemodialysis prescription next day for 6 hours with further improvement. Initial metformin levels were found to be 46 mg/l (therapeutic levels < 2 mg/l),later confirming the diagnosis. On the 3rd day, renal function started to improve with further reduction of serum metformin level to 1.5 mg/l. He was extubated on day 5 and subsequently discharged after making a complete recovery.Lactic acidosis is a rare and potentially lethal complication of metformin therapy. It is seen in 6.3 cases per 100,000 patients on treatment(1). It can be a consequence of acute overdose or secondary to impaired metformin renal clearance. Most of the patients with metformin induced lactic acidosis have other co-morbidities like cardiopulmonary or severe renal or liver disease. Volume depletion, use of drugs that interfere with renal autoregulation like angiotensin converting enzyme Inhibitors and nonsteroidal anti-inflammatory drugs can be contributory factors. The mechanism of action is th Continue reading >>

A Comparison Between The Effects Of Metformin And N -acetyl Cysteine (nac) On Some Metabolic And Endocrine Characteristics Of Women With Polycystic Ovary Syndrome

A Comparison Between The Effects Of Metformin And N -acetyl Cysteine (nac) On Some Metabolic And Endocrine Characteristics Of Women With Polycystic Ovary Syndrome

Full Terms & Conditions of access and use can be found at Download by: [Kashanian Maryam] Date: 25 December 2015, At: 00:26 ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: A comparison between the effects of metformin and N-acetyl cysteine (NAC) on some metabolic and endocrine characteristics of women with Forough Javanmanesh, Maryam Kashanian, Maryam Rahimi & Narges To cite this article: Forough Javanmanesh, Maryam Kashanian, Maryam Rahimi & Narges Sheikhansari (2015): A comparison between the effects of metformin and N-acetyl cysteine (NAC) on some metabolic and endocrine characteristics of women with polycystic ovary syndrome, Gynecological Endocrinology, DOI: 10.3109/09513590.2015.1115974 To link to this article: Department of Obstetrics & Gynecology, Firoozgar Teaching Hospital, Iran University of Medical Sciences, Tehran, Iran, & Gynecology, Akbarabadi Teaching Hospital, Iran University of Medical Sciences, Tehran, Iran, and Medicine, University of Southampton, Southampton, UK Objective: To compare N-acetyl cysteine (NAC) and metformin on polycystic ovary syndrome Method: Study was performed as a randomized double-blind clinical trial on women with diagnosis of PCOS without additional complications. In one group, oral NAC 600 mg, three times a day and in the other group, 500 mg oral metformin, three times a day were prescribed. Duration of treatment was 24 weeks, and after finishing this period of treatment, fasting blood glucose (FBS) and insulin, lipid profile and Homeostasis Model Assessment (HOMA) index were measured (all the blood samples were taken while fasting) and were compared in the two Results: Forty-six women in NAC group and 48 women in metformin group finished the study. The two groups did not show significant difference according to a Continue reading >>

The Toxicology Takedown #2 January 2015

The Toxicology Takedown #2 January 2015

The Toxicology Takedown #2 January 2015 A 15-Year-old female presents to the hospital 4 hours after ingestion of her diabetic fathers medication following a family dispute. Her family is unable to account for 75 x 5 mg glipizide and 29 x 500 mg metformin tablets. On arrival, she is vomiting and appears anxious and slightly sweaty with Glasgow Coma Score of 14/15. Her vital signs are pulse rate 90 bpm, blood pressure 110/75 mmHg, respiratory rate 18/min, and temperature of 36.8 C. A bedside blood glucose level is 54 mg/dl. Whats the immediate threat to life for this patient? Whats the mechanism of action of sulfonylurea medications, and how is it problematic in the management in toxicity? What are the antidotes for sulfonylurea toxicity? Whats concerning about metformin toxicity? What is the name of the syndrome that can develop in overdose and how it is managed? With respect to the ingestion of a potentially toxic amount of sulfonylureas, the immediate threat to life for this patient is hypoglycemia with potential progression to seizures and coma. This patient requires an IV line and administration of a bolus of 50 ml of 50% dextrose solution for correction of hypoglycemia and administration of another medication of minimize recurrent hypoglycemia. Glipizide is one of many sulfonylurea oral hypoglycemic agents. It exerts its effect by stimulating insulin release from the beta islet cells of the pancreas. All sulfonylureas inhibit ATP-sensitive K+ channels. This inhibition increases the membrane potential and depolarizes the cell. A subsequent influx of extracellular calcium ions through voltage-dependent calcium channels Occurs. An increase in the free intracellular calcium level is the signal, or second messenger, that triggers exocytosis and the release of insulin. F Continue reading >>

Overdose Of Oral Antidiabetic Medications And Insulin

Overdose Of Oral Antidiabetic Medications And Insulin

Overdose of Oral Antidiabetic Medications and Insulin Authors: Diana Strasburger, MD, RDMS, Attending Physician, Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, IL. Janna H. Villano, MD, Resident Physician, Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, IL. Peer Reviewer: Gina Piazza, DO, Associate Professor of Emergency Medicine, Georgia Health Sciences University, Augusta, GA. — Sandra M. Schneider, MD, Editor Treating the hypoglycemia and metabolic derangements caused by antidiabetic medications, especially in massive overdose, are dynamic as new agents are introduced. Emergency physicians should know potential pitfalls in order to effectively and safely manage these patients, avoiding rebound hypoglycemia and premature discharge without appropriate monitoring. This article will review the clinical presentation and management of toxicity from commercially available antidiabetic agents in the United States, including oral hypoglycemic agents such as sulfonylureas and oral antihyperglycemic agents such as biguanides, as well as novel antidiabetic agents and insulin. Introduction Diabetes mellitus (DM) is an ever-increasing epidemic facing the current health care system. Its prevalence is increasing worldwide from an estimated 30 million in 1985 to 150 million in 2000, 171 million in 2007, and an anticipated 366 million in 2030.1,2 Medications used to treat diabetes are diverse, and often patients use multiple classes of medications to obtain euglycemia. Oral preparations can be divided into two categories based on their pharmacodynamics and effect or lack of an effect on insulin: hypoglycemic agents such as sulfonylureas and meglitinides; and antihyperglycemic agents such as biguanides, alpha-glucosidase inhibi Continue reading >>

Metformin-related Acidosis In A Woman While Performing Haj: A Conservative Approach Ansari Rs, Mady Af, Qutub Ho, Althomaly E, Alzayer Za, Moulana Aa - Saudi J Kidney Dis Transpl

Metformin-related Acidosis In A Woman While Performing Haj: A Conservative Approach Ansari Rs, Mady Af, Qutub Ho, Althomaly E, Alzayer Za, Moulana Aa - Saudi J Kidney Dis Transpl

Metformin is a biguanide that enhances the release of glucose from the liver and the insulin effect on peripheral tissues thus decreasing the blood glucose. The most serious sideeffect of metformin is lactic acidosis due to inhibition of hepatic gluconeogenesis and/or reduction of conversion of lactic acid, pyruvic acid or alanine to glucose. The yearly incidence of lactic acidosis in previous reports was less than five episodes in every 100,000 treated individuals. Still, there is no particular antidote for metformin-induced lactic acidosis and its treatment mainly involves the correction of acidemia. [1] Considerable efficacy has been observed in the use of hemodialysis to treat the metformin-induced lactic acidosis. Hemodialysis application is currently recommended in patients with severe metabolic acidosis (pH < 7.1) and renal failure. It has been shown that plasma metformin concentrations are only slightly increased when the estimated glomerular filtration rate is 30 mL/ min/1.73 m2. [2] We present a case of successful management of metformin-associated metabolic acidosis, treated simply with intravenous sodium bicarbonate and aggressive hydration and intensive monitoring. Our aim in presenting this article is to demonstrate that even normal doses of metformin can induce severe acidosis. A 55-year-old woman with type 2 diabetes mellitus presented to the emergency department (ED) with altered level of consciousness. The patient was on metformin 500 mg three times a day. Her respiratory rate was 30 breaths/min, non-invasive blood pressure was 90/50 mm Hg, heart rate was 90 beats/min and temperature was 37C. The physical exam was otherwise unremarkable. The laboratory investigations [Table 1] on admission revealed plasma creatinine: 12.72 mg/dL, blood urea nitrogen: Continue reading >>

Metformin - National Library Of Medicine Hsdb Database

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 >>

A Pediatric Suicide Attempt By Ingestion Of Metformin, Glimepiride Andsulpiride: A Case Report And Literature Review

A Pediatric Suicide Attempt By Ingestion Of Metformin, Glimepiride Andsulpiride: A Case Report And Literature Review

Received date: March 01, 2016; Accepted date: July 04, 2016; Published date: July 11, 2016 Citation: Tarek G, Kais G, Ramzi G (2016) A Pediatric Suicide Attempt by Ingestion of Metformin, Glimepiride and Sulpiride: A Case Report and Literature Review. J Clin Toxicol 6:310. doi:10.4172/2161-0495.1000310 Copyright: 2016 Tarek G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. A case of a pediatric patient poisoning after ingestion of metformin , glimepiride and sulpiride, he was presented to the emergency service with symptoms and signs of hypoglycemia. Using a risk assessment based approach, the management of glimepiride and metformin overdose is discussed. Glimepiride overdose invariably results in profound hypoglycemia that requires resuscitation with IV dextrose and the use of octreotide as an antidote. Metformin overdose rarely causes problems. The acute sulpiride poisoning is poorly reported in the medical literature. Pediatric; Suicide attempt; Poisoning; Metformin; Glimepiride; Sulpiride Children suffering from physical, mental or psychological problems are being increasingly evaluated and treated in pediatric clinical [ 1 ]. Pediatric emergency departments frequently admit that a lot of children have attempted to commit suicide. Cases vary depending on both the child's age and some risk factors [ 2 ]. The main profile is a female between 12 and 14 years of age that attempted suicide at home using medication especially benzodiazepines. Among those under 10 years, there is a significant predominance of males using non pharmacological methods [ 3 ]. Understanding how childr Continue reading >>

Tennessee Poison Center - 03-23-17 How Does Metformin Differ From Other Oral Hypoglycemic Drugs? - Vanderbilt Health Nashville, Tn

Tennessee Poison Center - 03-23-17 How Does Metformin Differ From Other Oral Hypoglycemic Drugs? - Vanderbilt Health Nashville, Tn

03-23-17 How does Metformin differ from other oral hypoglycemic drugs? 03-23-17 How does Metformin differ from other oral hypoglycemic drugs? How does Metformin differ from other oral hypoglycemic drugs? Metformin is a biguanide agent and the drug-of-choice for the treatment of newly diagnosed type-2 diabetes mellitus, making it one of the most widely prescribed medications in the world. With over half a century of clinical experience, metformin is generally recognized as safe with the most frequent adverse effects being gastrointestinal (i.e. nausea, indigestion, abdominal cramps/bloating, diarrhea). Metformin acts to reduce hepatic glucose production, reduce intestinal glucose absorption, and increase skeletal muscle glucose uptake and utilization. Because it does not affect the release of insulin or other pancreatic hormones, metformin is rarely associated with hypoglycemia. Metformin impairs mitochondrial respiration and inhibits the conversion of lactate to pyruvate. This results in both an increased production and decreased elimination of lactate with a subsequent acidosis known as metformin-associated lactic acidosis (MALA). MALA is a serious but rare complication of metformin therapy (less than 10 events per 100,000 patient-years of exposure) with a mortality rate that approaches 50%. MALA as a result of therapeutic use is typically due to an acute event that affects the patients ability to excrete metformin (i.e. acute kidney injury) coupled with risk factors that increase lactate production and/or retention (see table below). Small changes in hydration, renal function, plasma metformin concentrations, and tissue oxygenation often lead into a positive feedback loop that worsens the lactic acidosis. Acute metformin overdose is the most frequent cause of MALA. S Continue reading >>

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