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What Is Lactic Acidosis And Metformin?

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 >>

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 >>

Side Effects Of Metformin: What You Should Know

Side Effects Of Metformin: What You Should Know

Metformin is a prescription drug used to treat type 2 diabetes. It belongs to a class of medications called biguanides. People with type 2 diabetes have blood sugar (glucose) levels that rise higher than normal. Metformin doesn’t cure diabetes. Instead, it helps lower your blood sugar levels to a safe range. Metformin needs to be taken long-term. This may make you wonder what side effects it can cause. Metformin can cause mild and serious side effects, which are the same in men and women. Here’s what you need to know about these side effects and when you should call your doctor. Find out: Can metformin be used to treat type 1 diabetes? » Metformin causes some common side effects. These can occur when you first start taking metformin, but usually go away over time. Tell your doctor if any of these symptoms are severe or cause a problem for you. The more common side effects of metformin include: heartburn stomach pain nausea or vomiting bloating gas diarrhea constipation weight loss headache unpleasant metallic taste in mouth Lactic acidosis The most serious side effect metformin can cause is lactic acidosis. In fact, metformin has a boxed warning about this risk. A boxed warning is the most severe warning from the Food and Drug Administration (FDA). Lactic acidosis is a rare but serious problem that can occur due to a buildup of metformin in your body. It’s a medical emergency that must be treated right away in the hospital. See Precautions for factors that raise your risk of lactic acidosis. Call your doctor right away if you have any of the following symptoms of lactic acidosis. If you have trouble breathing, call 911 right away or go to the nearest emergency room. extreme tiredness weakness decreased appetite nausea vomiting trouble breathing dizziness lighthea 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 >>

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 >>

Risk Of Fatal And Nonfatal Lactic Acidosis With Metformin Use In Type 2 Diabetes Mellitus

Risk Of Fatal And Nonfatal Lactic Acidosis With Metformin Use In Type 2 Diabetes Mellitus

Metformin, a medication used to lower glucose levels in patients with diabetes mellitus, has long been thought to increase the risk for a metabolic disorder known as lactic acidosis. This review summarised data from all known comparative and observational studies lasting at least one month, and found no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use, or in 55,451 patient-years for those not on metformin. Average lactate levels measured during metformin treatment were no different than for placebo or for other medications used to treat diabetes. In summary, there is no evidence at present that metformin is associated with an increased risk for lactic acidosis when prescribed under the study conditions. There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments. 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 >>

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 >>

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-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 >>

Does Metformin Cause Lactic Acidosis?

Does Metformin Cause Lactic Acidosis?

Lactic acidosis refers to the build up of the acid 'lactate' (also known as lactic acid) in the blood. We all produce lactic acid when breaking down sugar at times of stress and when we exercise vigorously. In some circumstances, too much lactic acid can build up in the blood. This happens particularly in situations where there is not enough oxygen in the blood, or the kidneys are not filtering out lactic acid as they should be. Examples of these situations are kidney failure, heart attacks and severe lung problems. If lactic acid builds up, this changes the pH of the blood and can be very dangerous. Although lactic acidosis is rare, it happens occasionally to very sick patients regardless of what medicines they are taking. Why might metformin increase the risk of lactic acidosis? In the 1970s, a medication called phenformin was removed from the market. This was because it was found to significantly increase the risk of lactic acidosis. Metformin is in the same family as phenformin (they are both biguanides), so as you can imagine, people wondered whether it might also increase the risk of lactic acidosis. What are the facts? In 50 years of using metformin there have been only 330 reported cases of lactic acidosis in people taking it. All the reported cases of lactic acidosis in people on metformin were in people who were extremely sick and might have had lactic acidosis due to their other problems, regardless of the fact that they were taking metformin. A large study (cochrane review) in 2010 found no cases of lactic acidosis in 347 trials reporting on people taking metformin (70,490 patient years of use). The same review found that lactic acid levels were the same in people whether they took metformin or not. What is the current thinking? The current thinking is that Continue reading >>

Metformin-associated Lactic Acidosis

Metformin-associated Lactic Acidosis

Summarized from Friesecke S, Abel P, Roser M. Outcome of severe lactic acidosis associated with metformin accumulation. Critical Care 2010; 14: R226-210 Metformin is an oral hypoglycemic drug that has long been employed in the treatment of type 2 diabetes; it is particularly widely prescribed for those diabetics who are obese. Very rarely, metformin use results in severe lactic acidosis, most often occurring in patients with reduced renal function. Although a very rare adverse effect, metformin-associated lactic acidosis (MALA) is significant because it has a high (30-50 %) mortality rate. Lactic acidosis (unrelated to metformin) is a relatively common occurrence among the critically ill and usually arises as a result of tissue hypoxia consequent on the inadequate perfusion associated with clinical shock. The list of severe acute illnesses/conditions that can result in lactic acidosis is long and includes severe sepsis (septic shock), severe trauma (hemorrhagic shock), anaphylactic shock, cardiac arrest and acute liver failure. In all of these cases prognosis is predicted by the severity of the lactic acidosis; the higher the peak serum lactate and the lower the blood pH falls, the greater is the risk of not surviving these acute illnesses. Although metformin is a very rare cause of lactic acidosis, it is almost invariably very severe. Curiously, however, as a recently published study has confirmed, the severity of MALA does not seem to predict outcome. This study is a retrospective analysis of all patients (n=197) admitted to one German medical intensive care unit during a 5-year period (2004-2008) with lactic acidosis (defined as serum lactate > 5 mmol/L and blood pH < 7.35). Of the 197 patients, 10 had suffered MALA and 187 had suffered lactic acidosis of other orig Continue reading >>

Metformin-related Lactic Acidosis: Is It A Myth Or An Underestimated Reality?

Metformin-related Lactic Acidosis: Is It A Myth Or An Underestimated Reality?

Keywords: Metformin-associated lactic acidosis (MALA) , metformin , acute kidney injury , hemodialysis , lactic acidosis , continuous renal replacement therapy Metformin, belonging to a class of drugs called biguanides, oral agents used in the management of non-insulin dependent diabetes mellitus, is the recommended first-line treatment for overweight patients with type 2 diabetes mellitus (T2DM), and accounts for one-third of all orally active diabetes drugs prescribed in the USA. The biguanide class also included phenformin and buformin, withdrawn from most pharmaceutical markets due to the elevated risk of causing lactic acidosis. 1 Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: Recovery after massive overdoses of metformin. Semin Dial. 2006;19:8083. [Crossref] , [PubMed] , [Web of Science ] , [Google Scholar] Metformin has multiple not been completely elucidated mechanisms of action. It reduces gluconeogenesis, increases peripheral uptake of glucose, and decreases fatty acid oxidation. From a pharmacokinetic point of view, metformin is little associated with plasma proteins and unmetabolized excreted in the urine, without direct nephrotoxic action. The half-life is approximately 6.5 h in individual with normal renal function, extending in patients with severe renal failure. 2 Frid A, Sterner GN, Lndahl M, etal. Novel assay of metformin levels in patients with type 2 Diabetes and varying levels of renal function: Clinical recommendations. Diabetes Care. 2010;33:12911293. [Crossref] , [PubMed] , [Web of Science ] , [Google Scholar] Recent studies have shown beneficial pleiotropic effects of metformin in patients with polycystic ovary syndrome 3 Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Wo 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 >>

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