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Lactic Acidosis Metformin

Metformin Associated Lactic Acidosis

Metformin Associated Lactic Acidosis

Emma Fitzgerald, specialist trainee year 2 in anaesthetics 1 , Stephen Mathieu, specialist registrar in anaesthetics and intensive care medicine 1 , Andrew Ball, consultant in anaesthesia and intensive care medicine 1 1Dorset County Hospital, Dorchester, Dorset DT1 2JY Correspondence to: E Fitzgerald zcharm6{at}hotmail.com Dehydration in patients taking metformin can lead to metformin associated lactic acidosis, a potentially fatal condition Metformin, a dimethylbiguanide, is a widely used oral antihyperglycaemic drug used in the long term treatment of type 2 diabetes mellitus. More recently it has also been used to improve fertility and weight reduction in patients with polycystic ovary syndrome. Many large studies have shown that intensive glucose control with metformin in overweight patients with type 2 diabetes is associated with risk reductions of 32% (P=0.002) for any diabetes related end point, 42% (P=0.017) for diabetes related death, and 36% (P=0.011) for all cause mortality compared with diet alone. 1 Furthermore, metformin reduces microvascular end points, and its degree of glycaemic control is similar to that sulphonylureas and insulin. Metformin is considered to be first line treatment in overweight patients with type 2 diabetes whose blood glucose is inadequately controlled by lifestyle interventions alone and should be considered as a first line glucose lowering treatment in non-overweight patients with type 2 diabetes because of its other beneficial effects. 2 It may also be useful in overweight patients with type 1 diabetes. A potential complication of metformin is the development of type B (non-hypoxic) lactic acidosis. Although metformin associated lactic acidosis is a rare condition, with an estimated prevalence of one to five cases per 100 000 popu Continue reading >>

Lactic Acidosis And The Relationship With Metformin Usage: Case Reports

Lactic Acidosis And The Relationship With Metformin Usage: Case Reports

Lactic acidosis (LA) is defined as a state of decreased systemic pH (pH <7.35) and an elevated plasma lactate concentration (>5 mmol/L). It remains the most common cause of metabolic acidosis in hospitalized patients. [1] A recent review summarized the major causes of LA and the presumed mechanisms. [2] Typically, LA is divided into disorders associated with tissue hypoxia (Cohen and Woods classification type A) and disorders in which tissue hypoxia is absent (type B). Type A LA may result from severe heart failure, sepsis, or cardiopulmonary arrest; type B can be caused by renal and hepatic failure, diabetes mellitus (DM), or drugs and toxins, including metformin, valproate, and anti-retroviral agents. [3,4] It has been reported that cardiogenic or hypovolaemic shock, severe heart failure, trauma, and sepsis are the most common causes of LA. [5] Lactate accumulation may be caused by increased production (i.e., increase glycolysis caused by hypoperfusion, hypoxaemia), decreased clearance (impaired hepatic metabolism or renal excretion), or a combination of both. [6] The exact pathophysiology of elevated lactate is likely to be the result of more than 1 condition. Many studies have shown that high lactate levels are associated with substantially increased mortality. [2,7,8] The mortality rate of LA has been reported to be between 50% and 83%. [911] DM has been also considered as one of the causes of LA. [2] The possible explanations include LA arising in patients with diabetic ketoacidosis, which is likely to be due to hypovolaemia [2] ; or reduced activity of pyruvate dehydrogenase, which may cause increased lactate levels in patients with DM independent of ketoacidosis. [12] In addition, diabetic patients with micro- or macrovascular disease are at an increased risk o Continue reading >>

Review Metformin-associated Lactic Acidosis: Current Perspectives On Causes And Risk

Review Metformin-associated Lactic Acidosis: Current Perspectives On Causes And Risk

Abstract Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (< 10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the resu Continue reading >>

Metformin And Fatal Lactic Acidosis

Metformin And Fatal Lactic Acidosis

Publications Published: July 1998 Information on this subject has been updated. Read the most recent information. Dr P Pillans,former Medical Assessor, Centre for Adverse Reactions Monitoring (CARM), Dunedin Metformin is a useful anti-hyperglycaemic agent but significant mortality is associated with drug-induced lactic acidosis. Significant renal and hepatic disease, alcoholism and conditions associated with hypoxia (eg. cardiac and pulmonary disease, surgery) are contraindications to the use of metformin. Other risk factors for metformin-induced lactic acidosis are sepsis, dehydration, high dosages and increasing age. Metformin remains a major reported cause of drug-associated mortality in New Zealand. Of the 12 cases of lactic acidosis associated with metformin reported to CARM since 1977, 2 occurred in the last year and 8 cases had a fatal outcome. Metformin useful but small risk of potentially fatal lactic acidosis Metformin is a useful therapeutic agent for obese non-insulin dependent diabetics and those whose glycaemia cannot be controlled by sulphonylurea monotherapy. Lactic acidosis is an uncommon but potentially fatal adverse effect. The reported frequency of lactic acidosis is 0.06 per 1000 patient-years, mostly in patients with predisposing factors.1 Examples of metformin-induced lactic acidosis cases reported to CARM include: A 69-year-old man, with renal and cardiac disease, was prescribed metformin due to failing glycaemic control on glibenclamide monotherapy. He was well for six weeks, then developed lactic acidosis and died within 3 days. Post-surgical lactic acidosis caused the death of a 70-year-old man whose metformin was not withdrawn at the time of surgery. A 56-year-old woman, with no predisposing disease, died from lactic acidosis following major Continue reading >>

Mala: Metformin-associated Lactic Acidosis

Mala: Metformin-associated Lactic Acidosis

By Charles W. O’Connell, MD Introduction Metformin is a first-line agent for type 2 diabetes mellitus often used as monotherapy or in combination with oral diabetic medications. It is a member of the biguanide class and its main intended effect is expressed by the inhibition of hepatic gluconeogenesis. In addition, metformin increases insulin sensitivity, enhances peripheral glucose utilization and decreases glucose uptake in the gastrointestinal tract. Phenformin, a previously used biguanide, as withdrawn from the market in the 1970’s due its association with numerous cases of lactic acidosis. Metformin is currently used extensively in the management of diabetes and is the most commonly prescribed biguanide worldwide. The therapeutic dosage of metformin ranges from 850 mg to a maximum of 3000 mg daily and is typically divided into twice daily dosing. It is primarily used in the treatment of diabetes but has been used in other conditions associated with insulin resistance such as polycystic ovarian syndrome. MALA is a rare but well reported event that occurs with both therapeutic use and overdose states. Case presentation A 22-year-old female presents to the Emergency Department after being found alongside a suicide note by her family. She was thought to have taken an unknown, but large amount of her husband’s metformin. She arrives at the ED nearly 10 hours after ingestion. She was agitated, but conversant. She reports having nausea and vague feelings of being unwell and is very distraught over the state of her critically ill husband. She has some self-inflicted superficial lacerations over her left anterior forearm. Her vital assigns upon arrival were: T 98.9 degrees Fahrenheit, HR initially 140 bpm which improved to 110 bpm soon after arrival, BP 100/50, RR 22, Continue reading >>

Should Dialysis Be Offered In All Cases Of Metformin-associated Lactic Acidosis?

Should Dialysis Be Offered In All Cases Of Metformin-associated Lactic Acidosis?

Should dialysis be offered in all cases of metformin-associated lactic acidosis? Metformin is commonly used in diabetes mellitus type 2, with lactic acidosis being a rare but potentially fatal complication of this therapy. The management of metformin-associated lactic acidosis (MALA) is controversial. Treatment may include supportive care, activated charcoal, bicarbonate infusion, hemodialysis, or continuous venovenous hemofiltration. In the previous issue of Critical Care, Peters and colleagues systematically evaluated outcomes in MALA patients admitted to their intensive care unit. The mortality rate of patients who received dialysis was similar to that of patients who were not dialyzed. However, it was the more acutely and chronically ill patients who actually received dialysis. This suggests that hemodialysis was beneficial in preventing a higher mortality rate in those who required renal replacement therapy. Diabetes Mellitus TypeMetforminRenal Replacement TherapyAcute Kidney InjuryActivate Charcoal The literature on the management of metformin-associated lactic acidosis (MALA) is sparse and consists of case reports and case series. In the previous issue of Critical Care, Peters and colleagues [ 1 ] presented a retrospective cohort study in patients with MALA. This study represents an important step forward in systematically evaluating outcomes in this rare but serious condition. Metformin is commonly used in type 2 diabetes mellitus and accounts for approximately one third of all prescriptions for oral hypoglycemic agents in the US [ 2 ]. The United Kingdom Prospective Diabetes Study demonstrated impressive reductions in diabetes-related endpoints and mortality in overweight patients with type 2 diabetes who used this drug [ 3 ]. A rare but extremely serious adve Continue reading >>

Metformin-induced Lactic Acidosis: No One Left Behind

Metformin-induced Lactic Acidosis: No One Left Behind

Metformin-induced lactic acidosis: no one left behind 1Centro Nazionale di Informazione Tossicologica - Centro Antiveleni, IRCCS Fondazione Salvatore Maugeri, Via S. Maugeri 10, 27100 Pavia, Italy 2Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Universit degli Studi di Milano, Via F.sco Sforza 35, 20122 Milano, Italy This article has been cited by other articles in PMC. Metformin is a safe drug when correctly used in properly selected patients. In real life, however, associated lactic acidosis has been repeatedly, although rarely, reported. The term metformin-induced lactic acidosis refers to cases that cannot be explained by any major risk factor other than drug accumulation, usually due to renal failure. Treatment consists of vital function support and drug removal, mainly achieved by renal replacement therapy. Despite dramatic clinical presentation, the prognosis of metformin-induced lactic acidosis is usually surprisingly good. In the previous issue of Critical Care, Friesecke and colleagues demonstrate that the survival rate of patients with severe lactic acidosis due to metformin accumulation can be strikingly higher than expected based on the initial clinical evaluation [ 1 ]. Metformin is nowadays the first-line drug of choice for the treatment of adults with type 2 diabetes [ 2 ]. This drug is the sixth most frequently prescribed in the USA (> 50 million prescriptions in 2009) and is taken by almost 1.5% of the Italian population [ 3 , 4 ]. Metformin is a safe drug when correctly used in properly selected patients. In particular, no cases of lactic acidosis (a relatively common side effect of other biguanide compounds) were reported in 347 trials with 70,490 patient-years of metformin use [ 5 ]. Real life can differ from research s Continue reading >>

Lactic Acidosis

Lactic Acidosis

The buildup of lactic acid in the bloodstream. This medical emergency most commonly results from oxygen deprivation in the body’s tissues, impaired liver function, respiratory failure, or cardiovascular disease. It can also be caused by a class of oral diabetes drugs called biguanides, which includes metformin (brand name Glucophage). Another biguanide called phenformin was pulled from the market in the United States in 1977 because of an unacceptably high rate of lactic acidosis associated with its use. Concerns about lactic acidosis also delayed the introduction of metformin to the U.S. market until 1995, despite the fact that it had been widely used for years in other countries. There have been reports of lactic acidosis occurring in people taking metformin, and the U.S. Food and Drug Administration estimates that lactic acidosis occurs in 5 out of every 100,000 people who use metformin for any length of time. However, this risk is much lower than it was in people taking phenformin, and it is not clear whether the episodes of lactic acidosis associated with metformin have actually been due to metformin use. In fact, the lactic acidosis could have been explained by the person’s diabetes and related medical conditions. Nonetheless, diabetes experts recommend that metformin not be used in people with congestive heart failure, kidney disease, or liver disease. They also recommend that it be discontinued (at least temporarily) in people undergoing certain medical imaging tests called contrast studies. Symptoms of lactic acidosis include feeling very weak or tired or having unusual muscle pain or unusual stomach discomfort. Continue reading >>

Lactic Acidosis: What You Need To Know

Lactic Acidosis: What You Need To Know

Lactic acidosis is a form of metabolic acidosis that begins in the kidneys. People with lactic acidosis have kidneys that are unable to remove excess acid from their body. If lactic acid builds up in the body more quickly than it can be removed, acidity levels in bodily fluids — such as blood — spike. This buildup of acid causes an imbalance in the body’s pH level, which should always be slightly alkaline instead of acidic. There are a few different types of acidosis. Lactic acid buildup occurs when there’s not enough oxygen in the muscles to break down glucose and glycogen. This is called anaerobic metabolism. There are two types of lactic acid: L-lactate and D-lactate. Most forms of lactic acidosis are caused by too much L-lactate. Lactic acidosis has many causes and can often be treated. But if left untreated, it may be life-threatening. The symptoms of lactic acidosis are typical of many health issues. If you experience any of these symptoms, you should contact your doctor immediately. Your doctor can help determine the root cause. Several symptoms of lactic acidosis represent a medical emergency: fruity-smelling breath (a possible indication of a serious complication of diabetes, called ketoacidosis) confusion jaundice (yellowing of the skin or the whites of the eyes) trouble breathing or shallow, rapid breathing If you know or suspect that you have lactic acidosis and have any of these symptoms, call 911 or go to an emergency room right away. Other lactic acidosis symptoms include: exhaustion or extreme fatigue muscle cramps or pain body weakness overall feelings of physical discomfort abdominal pain or discomfort diarrhea decrease in appetite headache rapid heart rate Lactic acidosis has a wide range of underlying causes, including carbon monoxide poisoni Continue reading >>

Glyburide And Metformin (oral Route)

Glyburide And Metformin (oral Route)

Precautions Drug information provided by: Micromedex It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects. Under certain conditions, too much metformin can cause lactic acidosis. The symptoms of lactic acidosis are severe and quick to appear. They usually occur when other health problems not related to the medicine are present and very severe, such as a heart attack or kidney failure. The symptoms of lactic acidosis include abdominal or stomach discomfort; decreased appetite; diarrhea; fast, shallow breathing; a general feeling of discomfort; muscle pain or cramping; and unusual sleepiness, tiredness, or weakness. If you have any symptoms of lactic acidosis, get emergency medical help right away. It is very important to carefully follow any instructions from your health care team about: Alcohol—Drinking alcohol may cause severe low blood sugar. Discuss this with your health care team. Other medicines—Do not take other medicines unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems. Counseling—Other family members need to learn how to prevent side effects or help with side effects if they occur. Also, patients with diabetes may need special counseling about diabetes medicine dosing changes that might occur because of lifestyle changes, such as changes in exercise and diet. Furthermore, counseling on contraception and pregnancy may be needed because of the problems that can occur in patients with diabetes during pregnancy. Travel—Keep your recent prescription and your medical history with yo Continue reading >>

Metformin-induced Lactic Acidosis With Emphasis On The Anion Gap

Metformin-induced Lactic Acidosis With Emphasis On The Anion Gap

Metformin-induced lactic acidosis with emphasis on the anion gap We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. Proceedings (Baylor University. Medical Center) Metformin-induced lactic acidosis with emphasis on the anion gap Britton Blough, MD, Amber Moreland, MD, and Adan Mora, Jr., MD The presence of an anion gap in a diabetic patient, especially if associated with evidence of compromised renal function, should prompt clinicians to consider metformin as a contributing factor. This consideration is especially important in patients with severe anion gaps associated with lactic acidosis out of proportion to the patient's clinical presentation. Measurement of serum electrolytes and determination of acid-base status is beyond routine in today's clinical practice. The importance of recognizing and treating disturbances in normal physiology cannot be overstated, as this information can provide clues to the existence of many reversible, yet if left untreated fatal, disease processes. The most commonly used scenario for calculating the serum anion gap (AG) is determining the etiology of metabolic acidosis ( Table 1 ). Disturbances of the AG can be seen in a variety of conditions, and if accurately recognized can yield critical diagnostic information. Presented is a case of compound AG acidosis. Causes of increased anion gap metabolic acidosis A 71-year-old woman with type 2 diabetes mellitus, hypertension, and coronary artery disease Continue reading >>

Lactic Acidosis Induced By Metformin: Incidence, Management And Prevention.

Lactic Acidosis Induced By Metformin: Incidence, Management And Prevention.

Abstract Lactic acidosis associated with metformin treatment is a rare but important adverse event, and unravelling the problem is critical. First, this potential event still influences treatment strategies in type 2 diabetes mellitus, particularly in the many patients at risk of kidney failure, in those presenting contraindications to metformin and in the elderly. Second, the relationship between metformin and lactic acidosis is complex, since use of the drug may be causal, co-responsible or coincidental. The present review is divided into three parts, dealing with the incidence, management and prevention of lactic acidosis occurring during metformin treatment. In terms of incidence, the objective of this article is to counter the conventional view of the link between metformin and lactic acidosis, according to which metformin-associated lactic acidosis is rare but is still associated with a high rate of mortality. In fact, the direct metformin-related mortality is close to zero and metformin may even be protective in cases of very severe lactic acidosis unrelated to the drug. Metformin has also inherited a negative class effect, since the early biguanide, phenformin, was associated with more frequent and sometimes fatal lactic acidosis. In the second part of this review, the objective is to identify the most efficient patient management methods based on our knowledge of how metformin acts on glucose/lactate metabolism and how lactic acidosis may occur (at the organ and cellular levels) during metformin treatment. The liver appears to be a key organ for both the antidiabetic effect of metformin and the development of lactic acidosis; the latter is attributed to mitochondrial impairment and subsequent adenosine triphosphate depletion, acceleration of the glycolytic flux Continue reading >>

Diabetes And Metformin Faqs

Diabetes And Metformin Faqs

Tweet Although one of the most common drugs for type 2 diabetics, Metformin can still confuse diabetic patients. This set of FAQs are intended for information purposes, and should not replace or supersede the advice of a doctor or qualified medical professional. If you have a question about diabetes and Metformin that is not covered here, please ask the community in the Diabetes forum. Should all type 2 diabetics take Meformin? One side effect of taking Metformin is lactic acidosis, and for this reason some diabetics should not take Metformin unless specifically advised to do so by their GP or diabetes healthcare team. For this reason, diabetics with kidney problems, liver problems, and heart problems are often advised to avoid Metformin. Similarly, diabetics that are dehydrated, drink alcohol a lot, or are going to have an x-ray or surgery. For some pregnant diabetics, Metformin may not be the best choice, but in all instances this should be discussed with your doctor. Can young diabetics take Metformin? Metformin has been proven in clinical trials to lower glucose levels amongst children between 10-16 years of age suffering from type 2 diabetes. Research is less conclusive about children under 10 and children taking Metformin alongside other treatments, but your diabetes health care team should be able to elaborate on this. How much Metformin should I take? This will depend entirely on your condition, and your doctor will be able to tell you how much Metformin to take, when you should take it, and how you should take it. Usually, diabetics start out on a low dose of Metformin, and this is slowly increased until blood sugar responds. Doctors often put diabetics on combination courses with other medication, including insulin. If I take Metformin, can I stop my diet and 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 >>

Is Metformin Associated With Lactic Acidosis?

Is Metformin Associated With Lactic Acidosis?

Is Metformin Associated With Lactic Acidosis? The use of metformin in patients with renal impairment is associated with an increased risk for lactic acidosis. Why is this and what is the mechanism? Are sulfonylureas associated with lactic acidosis? Adjunct Faculty, Albany College of Pharmacy, Albany, New York; Clinical Pharmacy Specialist, VA Medical Center, Bath, New York Metformin is one of most commonly prescribed medications for the treatment of type 2 diabetes mellitus. Metformin exerts its activity by increasing peripheral glucose uptake and utilization, and decreasing hepatic gluconeogenesis. By decreasing pyruvate dehydrogenase activity and mitochondrial reducing agent transport, metformin enhances anaerobic metabolism and increased production of tricarboxylic acid cycle precursors. Inhibition of pyruvate dehydrogenase subsequently decreases the channeling of these precursors into aerobic metabolism and causes increased metabolism of pyruvate to lactate and ultimately lactic acid production.[ 1 ] In a patient with normal renal function, the excess lactic acid is simply cleared through the kidneys. However, in a patient with renal impairment, both metformin and lactic acid are cleared less effectively and may result in further accumulation of both.[ 1 ] The complication of lactic acidosis is serious and potentially fatal. Increased risk for lactic acidosis associated with metformin is controversial. A Cochrane Systematic Review of over 200 trials evaluated the incidence of lactic acidosis among patients prescribed metformin vs non-metformin antidiabetes medications. Of 100,000 people, the incidence of lactic acidosis was 5.1 cases in the metformin group and 5.8 cases in the non-metformin group. The authors concluded that metformin is not associated with an incre Continue reading >>

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