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Lactic Acidosis Metformin Mechanism

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 Phenformin, a previously used biguanide, as withdrawn from the market in the 1970’s due its association with numerous cases of lactic acidosis.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 >>

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 In Metformin Therapy

Lactic Acidosis In Metformin Therapy

, Volume 58, Supplement1 , pp 5560 | Cite as The biguanide drugs metformin and phenformin have been linked in the past to lactic acidosis, a metabolic condition associated with high rates of mortality. Although concern over the hyperlactataemic effect of phenformin led to the withdrawal of this drug from clinical practice in the 1970s, the situation with metformin has been less clear. Retrospective data indicate that, in metformintreated patients with lactic acidosis, neither the degree of hyperlactataemia nor accumulation of metformin is of prognostic significance. Furthermore, the lowest rates of mortality were seen in patients with high plasma concentrations of metformin, which has led to the hypothesis that the drug may confer some benefit, linked to an increase in vasomotility, in such cases. Overall, it appears that mortality in patients receiving metformin who develop lactic acidosis is linked to underlying disease rather than to metformin accumulation, and that metformin can no longer be considered a toxic drug in this respect. These findings are likely to be of considerable relevance to the management of patients with type 2 (non-insulin-dependent) diabetes mellitus, especially where such patients are elderly. MetforminAdis International LimitedLactic AcidosisUnited Kingdom Prospective Diabetes StudyPhenformin These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves. This is a preview of subscription content, log in to check access Unable to display preview. Download preview PDF. Assan R, Heuclin C, Ganeval D, et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 1977; 13: 2117 PubMed CrossRef Google Scholar Fulop M, Hober 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 >>

Hyperglycaemic Crises And Lactic Acidosis In Diabetes Mellitus

Hyperglycaemic Crises And Lactic Acidosis In Diabetes Mellitus

Hyperglycaemic crises are discussed together followed by a separate section on lactic acidosis. DIABETIC KETOACIDOSIS (DKA) AND HYPERGLYCAEMIC HYPEROSMOLAR STATE (HHS) Definitions DKA has no universally agreed definition. Alberti proposed the working definition of “severe uncontrolled diabetes requiring emergency treatment with insulin and intravenous fluids and with a blood ketone body concentration of >5 mmol/l”.1 Given the limited availability of blood ketone body assays, a more pragmatic definition comprising a metabolic acidosis (pH <7.3), plasma bicarbonate <15 mmol/l, plasma glucose >13.9 mmol/l, and urine ketostix reaction ++ or plasma ketostix ⩾ + may be more workable in clinical practice.2 Classifying the severity of diabetic ketoacidosis is desirable, since it may assist in determining the management and monitoring of the patient. Such a classification is based on the severity of acidosis (table 1). A caveat to this approach is that the presence of an intercurrent illness, that may not necessarily affect the level of acidosis, may markedly affect outcome: a recent study showed that the two most important factors predicting mortality in DKA were severe intercurrent illness and pH <7.0.3 HHS replaces the older terms, “hyperglycaemic hyperosmolar non-ketotic coma” and “hyperglycaemic hyperosmolar non-ketotic state”, because alterations of sensoria may be present without coma, and mild to moderate ketosis is commonly present in this state.4,5 Definitions vary according to the degree of hyperglycaemia and elevation of osmolality required. Table 1 summarises the definition of Kitabchi et al.5 Epidemiology The annual incidence of DKA among subjects with type 1 diabetes is between 1% and 5% in European and American series6–10 and this incidence appear Continue reading >>

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

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

Metformin-associated lactic acidosis: Current perspectives on causes and risk. University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Elcelyx Therapeutics, Inc., San Diego, CA, USA. Elcelyx Therapeutics, Inc., San Diego, CA, USA. Electronic address: [email protected] Metabolism. 2016 Feb;65(2):20-9. doi: 10.1016/j.metabol.2015.10.014. Epub 2015 Oct 9. 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 diabete Continue reading >>

Metformin-associated Lactic Acidosis

Metformin-associated Lactic Acidosis

OVERVIEW metformin use is associated with lactic acidosis, but it remians controversial as a disease entity MECHANISM the mechanism of lactic acidosis is uncertain Metabolic effects of metformin include: decreased gluconeogenesis increased peripheral glucose uptake decreased fatty acid oxidation CLINICAL FEATURES presence of risk factors abdominal pain nausea and vomiting fatigue myalgias altered mental status myocardial insufficiency multi-organ failure RISK FACTORS advanced age high dose renal failure (metformin is excreted unchanged in the urine) hypoxia active alcohol intake sepsis dehydration shock acidosis INVESTIGATIONS high anion gap metabolic acidosis (HAGMA) high lactate MANAGEMENT rule out other causes of lactic acidosis (sepsis, cardiogenic shock, hypoperfusion, ischaemic bowel) withdrawal of metformin RRT RRT remove metformin and correct acidosis best performed early due to large volume of distribution of metformin use hemodialysis use HCO3 buffer CONTROVERSY Some argue that metformin itself does not cause lactic acidosis, that it is actually due to the underlying conditions such as renal failure and diabetes mellitus. However, there are definite cases of lactic acidosis from acute metformin overdose with no other underlying risk factors. References and Links Journal articles Orban JC, Fontaine E, Ichai C. Metformin overdose: time to move on. Crit Care. 2012 Oct 25;16(5):164. [Epub ahead of print] PubMed PMID: 23110819; PubMed Central PMCID: PMC3682282. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010 Apr 14;(4):CD002967. doi: 10.1002/14651858.CD002967.pub4. Review. PubMed PMID: 20393934. FOAM and web resources 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 >>

Metformin-associated Lactic Acidosis: Predisposing Factors And Outcome

Metformin-associated Lactic Acidosis: Predisposing Factors And Outcome

Go to: Abstract Metformin is considered the first choice oral treatment for type 2 diabetes patients in the absence of contraindications. Rarely, life-threatening complications associated with metformin treatment are seen in some patients with underlying diseases. The aim of this study was to further investigate the clinical profiles and risk factors for metformin-associated lactic acidosis (MALA) and the treatment modalities according to survival. To identify MALA, we performed a retrospective study in seven diabetic patients who were taking metformin and had been diagnosed with lactic acidosis at Inha University Hospital between 1995 and 2012. For each patient, we recorded the age, sex, daily metformin dosage, laboratory test results, admission diagnosis, and risk factors. Also, concurrent conditions, treatment modalities, and outcomes were evaluated. Six patients had risk factors for lactic acidosis before admission. All patients had renal impairment on admission as a precipitating risk factor. Five patients survived and two patients died despite early renal replacement therapy. Older patients tended to have a poorer prognosis. Renal function must be monitored in elderly type 2 diabetes mellitus patients with underlying diseases and conditions causing renal impairment who begin metformin treatment. Accurate recognition of MALA and initiation of renal replacement are essential for treatment. Keywords: Metformin, Acidosis, lactic, Diabetes mellitus, type 2 Go to: INTRODUCTION Metformin is an oral antidiabetic drug in the biguanide class that is widely used, alone or in combination with a sulfonylurea or other drugs, in patients with type 2 diabetes. The drug's glucose-lowering effect results mainly from decreased hepatic glucose output with increased glucose utilizatio Continue reading >>

Does Metformin Increase The Risk Of Fatal Or Nonfatal Lactic Acidosis?

Does Metformin Increase The Risk Of Fatal Or Nonfatal Lactic Acidosis?

WILLIAM E. CAYLEY, JR., MD, MDiv, University of Wisconsin Department of Family Medicine, Eau Claire, Wisconsin Am Fam Physician. 2010 Nov 1;82(9):1068-1070. Clinical Scenario A 70-year-old woman with type 2 diabetes mellitus who is in otherwise good health is experiencing gradually increasing glucose levels. Her physician considers starting her on an oral diabetes agent, but is concerned that her age may put her at risk for adverse effects if she is treated with metformin (Glucophage). Clinical Question Does metformin increase the risk of fatal or nonfatal lactic acidosis? Evidence-Based Answer In patients without standard contraindications to metformin therapy, metformin does not increase the risk of lactic acidosis.1 (Strength of Recommendation = B, based on inconsistent or limited-quality patient-oriented evidence) Practice Pointers The first-line treatments recommended for type 2 diabetes are lifestyle changes and metformin, which is a biguanide antihyperglycemic agent.2 Demonstrated benefits of metformin include lower cardiovascular mortality than other oral diabetes medications3 and a reduced risk of death or myocardial infarction in overweight patients with type 2 diabetes.4 However, because an earlier biguanide, phenformin, was removed from the market after being linked to several cases of lactic acidosis, there have been concerns that metformin may predispose patients to lactic acidosis as well. In light of this, metformin is considered contraindicated in patients with chronic renal insufficiency, pulmonary disease, or hypoxic conditions; abnormal hepatic function; peripheral vascular disease; and in those older than 65 years. The use of metformin in patients with heart failure continues to be controversial.1 The authors of this Cochrane review found no cases o Continue reading >>

Lactic Acidosis Secondary To Metformin Overdose: A Case Report

Lactic Acidosis Secondary To Metformin Overdose: A Case Report

Lactic acidosis secondary to metformin overdose: a case report 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. Lactic acidosis secondary to metformin overdose: a case report Simon Timbrell, Gary Wilbourn, [...], and Alan Liddle Metformin is a commonly used treatment modality in type 2 diabetes mellitus, with a well documented side effect of lactic acidosis. In the intensive care setting lactate and pH levels are regularly used as a useful predictor of poor prognosis. In this article we highlight how high lactate levels are not an accurate predictor of mortality in deliberate metformin overdose. We present the case of a 70-year-old Caucasian man who took a deliberate metformin overdose of unknown quantity. He had a profound lactic acidosis at presentation with a pH of 6.93 and a lactate level of more than 20mmol/L. These figures would normally correspond with a mortality of more than 80%; however, with appropriate management this patients condition improved. We provide evidence that the decision to treat severe lactic acidosis in deliberate metformin overdose should not be based on arterial lactate and pH levels, as would be the case in other overdoses. We also demonstrate that appropriate treatment with hemodiafiltration and 8.4% sodium bicarbonate, even in patients with a very high lactate and low pH, can be successful. Metformin is a biguanide typically used as a first line drug for the treatment of type 2 diabetes mellitus. I 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 >>

Metformin-induced Lactic Acidosis: No One Left Behind

Metformin-induced Lactic Acidosis: No One Left Behind

Abstract 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 settings, however, and lactic acidosis has been repeatedly, although rarely, observed in patients treated with metformin. The number of inquiries to the Swedish Poison Information Centre for metformin intoxication has increased 10 times during the past decade, with 25 cases of severe lactic acidosis reported in 2007 and 2008 [6]. According to the American Association of Poison Control Centers, metform 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 >>

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 >>

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