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.
Ethical Approval Trail Registration And Patient Involvement
The study was approved by the Danish Data Protection Agency and by the Danish National Board of Health . According to Danish law, no ethical approval is needed for registry-based studies . The work complies with the and has been conducted according to internationally accepted ethical standards. Patients, patient lawyers, and patient organizations were not involved in this research.
Types Of Lactic Acidosis
Cohen and Woods divided lactic acidosis into 2 categories, type A and type B.
Type A is lactic acidosis occurring in association with clinical evidence of poor tissue perfusion or oxygenation of blood . It can be caused by the overproduction of lactate or the underutilization of lactate. In cases of overproduction, circulatory, pulmonary, and hemoglobin transfer disorders are commonly responsible.
In cases of underutilization of lactate, liver disease, gluconeogenesis inhibition, thiamine deficiency, and uncoupled oxidative phosphorylation can be responsible.
Type B is lactic acidosis occurring when no clinical evidence of poor tissue perfusion or oxygenation exists. However, in many cases of type B lactic acidosis, occult tissue hypoperfusion is now recognized to accompany the primary etiology.
Type B is divided into 3 subtypes based on underlying etiology.
Type B1 occurs in association with systemic disease, such as renal and hepatic failure, diabetes and malignancy.
Type B2 is caused by several classes of drugs and toxins, including biguanides, alcohols, iron, isoniazid, zidovudine, and salicylates.
Type B3 is due to inborn errors of metabolism.
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Metabolic Aspects Of Lactate Production
The arterial concentration of lactate depends on the rates of its production and use by various organs. Blood lactate concentration normally is maintained below 2 mmol/L, although lactate turnover in healthy, resting humans is approximately 1300 mmol every 24 hours. Lactate producers are skeletal muscle, the brain, the gut, and the erythrocytes. Lactate metabolizers are the liver, the kidneys, and the heart. When lactate blood levels exceed 4 mmol/L, the skeletal muscle becomes a net consumer of lactate.
As mentioned above, lactate is a byproduct of glycolysis it is formed in the cytosol catalyzed by the enzyme lactate dehydrogenase, as shown below:
Pyruvate + NADH + H+ = lactate + NAD+
This is a reversible reaction that favors lactate synthesis with the lactate-to-pyruvate ratio that is normally at 25:1. Lactate synthesis increases when the rate of pyruvate formation in the cytosol exceeds its rate of use by the mitochondria. This occurs when a rapid increase in metabolic rate occurs or when oxygen delivery to the mitochondria declines, such as in tissue hypoxia. Lactate synthesis also may occur when the rate of glucose metabolism exceeds the oxidative capacity of the mitochondria, as observed with administration of catecholamines or errors of metabolism.
Box : Diagnostic Pitfalls In Dka
Sodium: whole body sodium is depleted but may appear:
Raised due to dehydration.
Cannot interpret temperature as marker of infection .
Pancreatitis can precipitate DKA but amylase is raised in the absence of pancreatitis in DKA .
Grossly raised triglycerides can cause pancreatitis and thus DKA but triglycerides are raised in DKA .
3-hydroxybutyrate concentrations in plasma are 23 times those of acetoacetate but in acidotic states this ratio is increased further. As therapy improves acidosis, levels of acetoacetate rise and methods that measure only acetoacetate concentration is urine may therefore suggest that ketonaemia is worsening.
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What Are The Symptoms Of Lactic Acidosis
Symptoms of lactic acidosis include feeling very weak or tired or having unusual muscle pain or unusual stomach discomfort.
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Lactic Acidosis Associated With Metformin In A Patient With Type 2 Diabetes With No Contraindication
Metformin is a frequent treatment for overweight type 2 patients with diabetes. Lactic acidosis is considered to be a rare, but potentially lethal adverse event associated with metformin. We describe a 52-year-old diabetic patient, with no contraindication to metformin, who had an unequivocal episode of LA related to the drug. After intensive supportive treatment, a fast recovery was observed. Considering putative benefits attributed to metformin, contraindications to this drug are being debated. The association of metformin with LA should be kept in mind when dealing with acute situations such as that presented by the patient described. From the Endocrine Division, Hospital de Clnicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Reprints: Jos Miguel Dora, MD, Servio de Endocrinologia, Hospital de Clnicas de Porto Alegre, Ramiro Barcelos 2350, 90035-003, Porto Alegre, RS, Brazil. E-mail: 2009 Lippincott Williams & Wilkins, Inc. Thought you might appreciate this item I saw at The Endocrinologist. Your message has been successfully sent to your colleague. Some error has occurred while processing your request. Please try after some time.Continue reading > >
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What Is Lactic Acidosis
Lactic acidoses is the buildup of lactic acid in the bloodstream. This medical emergency most commonly results from oxygen deprivation in the bodys 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 .
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.
Lactic Acidosis Rates In Type 2 Diabetes
Jonathan B Brown, Kathryn Pedula, Joshua Barzilay, Michael K Herson, Peggy Latare Lactic Acidosis Rates in Type 2 Diabetes. Diabetes Care 1 October 1998 21 : 16591663.
To provide a context for the interpretation of lactic acidosis risk among patients using metformin, we measured rates of lactic acidosis in patients with type 2 diabetes before metformin was approved for use in the U.S.
Using electronic databases of hospital discharge diagnoses and laboratory results maintained by a large, nonprofit health maintenance organization , we identified possible lactic acidosis events in three geographically and racially diverse populations with type 2 diabetes. We then reviewed hard-copy clinical records to confirm and describe each event and determine its likely cause.
From < 41,000 person-years of experience, we found four confirmed, three possible, and three borderline cases of lactic acidosis. In each case, we identified at least one severe medical condition that could have caused the acidosis. The annual confirmed event rate is similar to published rates of metformin-associated lactic acidosis.
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Causes Of Lactic Acidosis
INTRODUCTION AND DEFINITION Lactate levels greater than 2 mmol/L represent hyperlactatemia, whereas lactic acidosis is generally defined as a serum lactate concentration above 4 mmol/L. Lactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. Although the acidosis is usually associated with an elevated anion gap, moderately increased lactate levels can be observed with a normal anion gap . When lactic acidosis exists as an isolated acid-base disturbance, the arterial pH is reduced. However, other coexisting disorders can raise the pH into the normal range or even generate an elevated pH. Lactic acidosis occurs when lactic acid production exceeds lactic acid clearance. The increase in lactate production is usually caused by impaired tissue oxygenation, either from decreased oxygen delivery or a defect in mitochondrial oxygen utilization. The pathophysiology and causes of lactic acidosis will be reviewed here. The possible role of bicarbonate therapy in such patients is discussed separately. PATHOPHYSIOLOGY A review of the biochemistry of lactate generation and metabolism is important in understanding the pathogenesis of lactic acidosis . Both overproduction and reduced metabolism of lactate appear to be operative in most patients. Cellular lactate generation is influenced by the “redox state” of the cell. The redox state in the cellular cytoplasm is reflected by the ratio of oxidized and reduced nicotine adContinue reading > >
Lactic Acidosis In Diabetic Population: Is Metformin Implicated Results Of A Matched Case
1Centre Régional de Pharmacovigilance, Pôle Santé Publique, Centre Hospitalier Universitaire de Grenoble, 38000 Grenoble, France
2Service de Biostatistique des Hospices Civils de Lyon, 69002 Lyon, France
3Laboratoire Biostatistique Santé, UCBL, Equipe de lUMR CNRS 5558, 69495 Pierre-Bénite Cedex, France
4Pôle Pharmacie, Centre Hospitalier Universitaire de Grenoble, 38000 Grenoble, France
5Université Grenoble Alpes, 38000 Grenoble, France
According to the World Health Organization, diabetic population should reach almost 600 million worldwide, in 2035 . When medication is required, metformin is the first-line treatment in type 2 diabetes due to its superiority in reducing cardiovascular events and morbidity-mortality, compared to insulin and sulfonylureas .
The safety profile of metformin is well established: gastrointestinal disorders are the most frequent adverse effect. Lactic acidosis is a very rare but potentially severe adverse effect resulting from hepatic gluconeogenesis and mitochondrial respiration inhibition.
The mortality associated with this rare adverse drug effect is 50% with all biguanides . Recently, it was estimated to be around 26 to 30% with metformin . When measured, plasmatic level of metformin is difficult to interpret its correlation with lactate levels has not been demonstrated . In case of LA, metformin level is significantly higher in survivors than in nonsurvivors .
2.1. Population, Cases, and Controls
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Incidence Of Lactic Acidosis In Patients With Type 2 Diabetes With And Without Renal Impairment Treated With Metformin: A Retrospective Cohort Study
Florent F. Richy, Meritxell Sabidó-Espin, Sandra Guedes, Frank A. Corvino, Ulrike Gottwald-Hostalek Incidence of Lactic Acidosis in Patients With Type 2 Diabetes With and Without Renal Impairment Treated With Metformin: A Retrospective Cohort Study. Diabetes Care 1 August 2014 37 : 22912295.
To determine whether the use of metformin in type 2 diabetic patients with various kidney functions is associated with an increased risk of lactic acidosis .
This study was a retrospective analysis of U.K. patient records from the Clinical Practice Research Datalink database from 1 January 2007 to 31 December 2012. Inclusion criteria were 1) diagnosis of type 2 diabetes before 1 January 2007, 2) treatment with metformin, and 3) at least one assessment of renal function between 2007 and 2012. Renal function was assessed by glomerular filtration rate and categorized as normal , mildly reduced , moderately reduced , or severely reduced function. The outcome of the study was LA.
A total of 77,601 patients treated with metformin for type 2 diabetes were identified. There were 35 LA events of which none were fatal and 23 were linked to a comorbidity. No significant difference in the incidence of LA was observed across N, Mi, Mo and Se renal function groups .
Limitations Of Lactic Acidosis As A Monitor Of Tissue Perfusion
The use of lactate as an index of tissue perfusion has several limitations. The presence of liver disease causes a decreased ability to clear lactate during periods of increased production. Various causes of type B lactate acidosis may produce hyperlactemia and lactate acidosis in the absence of inadequate tissue perfusion. For significant increase in blood lactate to occur, lactate must be released into the systemic circulation and the rate of production must exceed hepatic, renal, and skeletal muscle uptake. Therefore, regional hypoperfusion of tissues may be present despite normal blood lactate concentrations.
Lactic acid levels can also lag several hours after the oxygen delivery critical threshold has been crossed. Indeed, patients may be accruing a significant amount of oxygen debt before lactate levels start to increase. It has been demonstrated that mixed venous saturation can fall below 50% before serum hyperlactatemia is evident.
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Metformin As A Cause Of Lactic Acidosis
Galega officinalis was recognized in medieval times as a treatment for diabetes mellitus . On the basis of the discovery of its active ingredient, guanidine, several drugs of the biguanide class were formulated to treat diabetes mellitus beginning in the 1950s . The first drug of this class in wide use, phenformin, was withdrawn from the United States market in the 1970s because of an unacceptably high incidence of lactic acidosis. Phenformin is highly lipid soluble and caused lactic acidosis by crossing the mitochondrial membrane and inhibiting mitochondrial oxidative phosphorylation and also, by inhibiting gluconeogenesis . Its descendent, metformin, lacks phenformins lipid solubility. It was introduced to the United States market in 1995 after studies showed a 10- to 20-fold reduction in the predisposition to lactic acidosis .
Metformin is an insulin sensitizer it is ineffective in the absence of insulin. It acts mainly by reducing hepatic gluconeogenesis , in large part by inhibiting mitochondrial oxidative phosphorylation and mitochondrial glycerophosphate dehydrogenase . It also has some effect to increase peripheral glucose disposal . Unlike phenformin, metformin is not metabolized and is eliminated entirely by the kidney. Its plasma clearance is by glomerular filtration and to a greater extent, tubular secretion through a variety of transporters . Despite a tremendous volume of distribution, its half-time of elimination is estimated to be only 2.7 hours .
Access And Sharing Of Data And Materials
Please contact the Research Service at the Department of Clinical Research, University of Southern Denmark, 5000 Odense C. Phone: +45 6550 4051. Up-to-date information on data access is available online:
a. Matched by age and sex in a risk-set manner.
b. Matched by age and sex and adjusted for Charlson comorbidity index, eGFR, HbA1c and diabetes duration
c. No-use of metformin is never use of metformin or occurrence of a metformin prescription dated more than 365 days before admission with lactic acidosis.
d. Recent use of metformin is occurrence of a metformin prescription in the past dated 91 to 365 days before admission with lactic acidosis.
e. Current use is occurrence of a metformin prescription within the past dated 90 days before admission with lactic acidosis.
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Incidence Rate Of La By Ckd
The incidence rates of LA stratified by kidney function are shown in . The overall incidence of LA in patients receiving metformin was 10.37 per 100,000 patient-years . No significant difference in the incidence of LA was observed across normal, mild, moderate, and severe renal function groups . The incidence rate ratios for metformin-treated patients with severely, moderately, and mildly reduced kidney function compared with patients with normal kidney function were 5.26 , 2.27 , and 0.61 , respectively .
Cellular Energy Metabolism And Lactate Production
Cells require a continuous supply of energy for protein synthesis. This energy is stored in the phosphate bonds of the ATP molecule. The hydrolysis of ATP results in the following reaction, where ADP is adenosine diphosphate and Pi is inorganic phosphate:
ATP = ADP + Pi + H+ + energy
With an adequate supply of oxygen, the cells use ADP, Pi, and H+ in the mitochondria to reconstitute ATP. During cellular hypoxia, the hydrolysis of ATP leads to accumulation of H and Pi in the cytosol. Therefore, ATP hydrolysis is the source of cellular acidosis during hypoxia and not the formation of lactate from glucose, which neither consumes nor generates H+. The glycolytic process may be viewed as the following:
D glucose + 2 ADP + 2 Pi = 2 lactate + 2 ATP
The hydrolysis of 2 ATP molecules formed from the metabolism of glucose produces H+, ADP, and Pi, as follows:
2 ATP = 2 ADP + 2 Pi + 2 H+ + energy
If the oxygen supply is adequate, the metabolites of ATP are recycled in the mitochondria and the cytosolic lactate concentration rises without acidosis. On the other hand, with cellular hypoxia, the equation of anaerobic glycolysis becomes the following:
D glucose = 2 lactate + 2 H+ + energy
A second cellular source of anaerobic ATP is the adenylate kinase reaction, also called the myokinase reaction, where 2 molecules of ADP join to form ATP and adenosine monophosphate .
ADP = AMP + Pi + H+ + energy
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Lactate Acidosis As A Metabolic Monitor Of Shock
Shock currently is conceptualized as a clinical syndrome resulting from an imbalance between tissue oxygen demands and tissue oxygen supply. Impaired oxygen delivery is the primary problem in hypovolemic, cardiogenic, distributive , and obstructive forms of shock. When tissue hypoxia is present, pyruvate oxidation decreases, lactate production increases, and ATP formation continues via glycolysis. The amount of lactate produced is believed to correlate with the total oxygen debt, the magnitude of hypoperfusion, and the severity of shock. Serial lactate determinations may be helpful in patients resuscitated from shock to assess the adequacy of therapies.
Lactic Acidosis In A Patient With Type 2 Diabetes Mellitus
Clin J Am Soc Nephrol. 2015 Aug 7 10:1476-83. doi: 10.2215/CJN.10871014. Epub 2015 Mar 11. Lactic Acidosis in a Patient with Type 2 Diabetes Mellitus. Division of Nephrology, Cooper Medical School of Rowan University, Cooper University Health Care, Camden, New Jersey Lactic acidosis occurs when lactate production exceeds its metabolism. There are many possible causes of lactic acidosis, and in any given patient, several causes may coexist. This Attending Rounds presents a case in point. Metformin’s role in the pathogenesis of lactic acidosis in patients with diabetes mellitus is complex, as the present case illustrates. The treatment of lactic acidosis is controversial, except for the imperative to remedy its underlying cause. The use of sodium bicarbonate to treat the often alarming metabolic derangements may be quite efficacious in that regard but is of questionable benefit to patients. Renal replacement therapies have particular appeal in this setting for a variety of reasons, but their effect on clinical outcomes is untested. acidosis congestive heart failure diabetes mellitus dialysis intoxicationContinue reading > >
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