Incidence Of Metformin-associated Lactic Acidosis Research Articles

Metformin-Associated Lactic Acidosis-Is This on Your Radar?

Background: Metformin is a biguanide hyperglycemic agent used to manage non–insulin-dependent diabetes mellitus. Adverse reactions include mainly mild gastrointestinal adverse effects, but severe complications, such as metformin-associated lactic acidosis (MALA) can occur. Metformin is excreted renally and, therefore, not recommended in patients with renal impairment. The reported incidence of MALA is 3 cases per 100,000 patient-years. Case ReportA 79-year-old woman with a complex medical history, including end-stage renal disease on dialysis and type 2 diabetes, presented to the emergency department (ED) for altered mental status. Prior to arrival, she was found to be hypoglycemic. Her laboratory results were significant for creatinine of 6.56 mg/dL and an anion gap of 52 mmol/L. The venous blood gas revealed a venous pH of 6.857 [reference range (7.32–7.43)], pCO2 of 15.9 mm Hg (40.6–60 mm Hg), HCO3 of 2.7 mmol/L (21–30 mmol/L), lactate of 27 mmol/L (0.5–2 mmol/L), and ammonia of 233 µmol/L. The patient was dialyzed emergently in the ED; repeat laboratory test results showed blood urea nitrogen of 10 mg/dL, creatinine of 1.65 mg/dL, carbon dioxide of 26 mmol/L, and anion gap of 13 mmol/L. The repeat ammonia was 16 µmol/L. The patient's metabolic encephalopathy resolved, and she was discharged home on hospital day 3. Why Should an Emergency Physician Be Aware of This?MALA has a high mortality rate (36%). Laboratory markers have not been found to be a reliable predictor of mortality. Sodium bicarbonate is controversial, but a pH < 7.15 indicates consideration of its use. A pH < 7.1 and a lactate level > 20 mmol/L indicate the need for emergent hemodialysis. Prompt recognition and management in the ED with early hemodialysis can result in good patient outcomes, with a return to their baseline function despite severe laboratory findings.

SAT136 Severe Lactic Acidosis Due To Metformin Use.

Abstract Disclosure: A. Khan: None. Lactic acidosis is an important cause of metabolic acidosis. Broadly, etiology can be divided into type A (impaired tissue oxygenation), type B (systemic hypoperfusion), and D-lactic acidosis. One such etiology which deserves mentioning is metformin associated lactic acidosis (MALA). The incidence of MALA is more notable in the setting of kidney dysfunction, hepatic failure, and alcohol use. Severe acidosis due to Metformin is an emergency and warrants timely management to avoid further hemodynamic compromise. 73-year-old female with a history of hypertension and type II diabetes mellitus (on metformin) presented to the hospital with acute onset of abdominal pain, nausea, and vomiting. She reported having intermittent vomiting and diarrhea for three days prior to admission, and describes the abdominal pain as 10/10, sharp with radiation to the lower back, and worsening 6 hours prior to arrival. She denies fever, melena, hematochezia, change in appetite. She was brought to the hospital via EMS and was given fentanyl for her pain. Vitals on arrival were stable. On exam, she appeared in distress due to pain, with diffuse tenderness in her abdomen, with normal cardiac and lung exam. Labs showed leukocytosis 15 K/mm3, hemoglobin 11.1 gm/dl, hyperkalemia 5.7 mEq/L, bicarb &amp;lt;5 mEq/L, creatinine 13.4 mg/dl, BUN 107 mg/dl, venous lactate 15.1 mmol/l, lipase 435 U/L, ammonia 229 umol/L, with normal AST, ALT and ALP, and troponin. Urinalysis was negative. Initial ABG showed an unreadable pH, which was then repeated, and pH was noted to be 6.72, pCO2 of 29.4 mm/hg, CTA angiography was negative for dissection, mesenteric or bowel ischemia. Soon she was noted to be hypotensive and went into shock requiring pressors, bicarbonate drip, and broad-spectrum antibiotics. She eventually was intubated for airway protection. Subsequently, she was admitted to the ICU for possibly combined hypovolemic and septic shock with multi-organ dysfunction, severe lactic acidosis, acute kidney failure, and respiratory failure. Nephrology was consulted and dialysis was initiated. It was postulated that the presentation was likely due to metformin associated lactic acidosis (MALA). She required dialysis daily for 4 days and ultimately her kidney function improved. On discharge, she was not dialysis dependent. The case above illustrates the severity of lactic acidosis that can occur due to Metformin use. It is important to bear in mind that such presentation, may not necessarily occur on initiation of Metformin, but rather at any point of use. More importantly, its of utmost importance to consider effective therapeutic options like dialysis once severe academia is noted to allow correction of metformin induced acid-base disorder. Mortality estimates of MALA have been around 25-50%, highlighting the significance of prompt treatment of this condition. Presentation: Saturday, June 17, 2023

Shouldn’t Stage 4 And 5 Chronic Kidney Disease Patients Use Metformin?

Metformin tip 2 diyabetes mellitus (DM) tanılı hastaların tedavisi için birçok kılavuzda yaşam tarzı değişikliği ile birlikte ilk sırada önerilen anti diyabetik ajandır. İlacın etki mekanizması periferik dokuda insülin duyarlılığını arttırması ve karaciğerden glukoz salınımını azaltmasıdır. Metformin düşük maliyetli, etkin ve güvenilir bir ilaçtır. Sık yan etkisi gastrointestinal yan etkiler olması yanında en korkulan yan etkisi laktik asidozdur. Bu yan etkisi nedeniyle kronik böbrek hastalığı (KBH) tanılı hastalarda birçok klavuzda kullanımı sınırlandırılmıştır. Biz bu yazıda KBH’nin her evresinde metformin kullanımını inceledik. Metfomin ilişkili laktik asidoz (MALA) gelişim sıklığını araştırdık. Evre 4 ve evre 5 KBH hastaları metformin kullanmamalı mı? Sorusuna cevap aradık. Sonuç olarak MALA gibi yan etkilerin son derece nadir olduğuna karar verdik. Bu yan etkilerin daha çok enfeksiyon, ciddi kardiyovasküler olay, hipotansiyon gibi doku perfüzyonunun bozulduğu hastalıklar varlığında ortaya çıktığını gözlemledik. Dolayısıyla metformin kullanımının MALA gibi yan etkilerden ziyade hastanın klinik durumunun stabil olmadığı durumlarda ve ilacın artmış birikim riski nedeniyle özellikle evre 5 hastalarda kontrendike olabileceği kanaatine vardık.vre 4 ve evre 5 KBY’li hastalarda çok da korkmadan kar zarar ilişkisi göz önünde bulundurularak kullanılması gerekliliği kanaatine vardık.

Renal Complications after Percutaneous Coronary Interventions on Concurrent Metformin Therapy: A Systematic Review with Meta-Analysis.

Objective: Metformin, commonly prescribed in diabetic patients, can cause lactic acidosis. Although generally rare, this side effect remains a source of concern in procedures requiring contrast media, due to the risk of contrast-induced nephropathy. Temporarily withdrawing metformin during the peri-procedural period is often practiced, but clinical decisions are difficult in emergency situations, such as acute coronary syndromes. In this systematic review with meta-analysis, we aimed to further investigate the safety of percutaneous coronary interventions in patients on concurrent metformin therapy.Design, Setting and Participants: We analyzed studies in patients undergoing (elective or emergency) percutaneous coronary interventions with or without concurrent metformin administration, reporting on the incidence of metformin-associated lactic acidosis and peri-procedural renal function.Methods: PubMed, ClinicalTrials.gov, Cochrane Library, and Scopus were systematically searched without language restrictions throughout August 2022. Randomized clinical trials and observational studies were assessed with the Revised Cochrane Collaboration Risk of Bias tool and the Newcastle-Ottawa quality scale, respectively. Data synthesis addressed the mean drop in estimated glomerular filtration rate (eGFR) and the incidence of contrast-induced nephropathy, in addition to lactic acidosis.Results: Nine studies were included, totaling 2235 patients (1076 continuing metformin during the peri-procedural period), mostly with eGFR above 30 mL/min/1.73m2 No cases of lactic acidosis were reported. The mean post-procedural drop in eGFR was 6.81mL/min/1.73m2 (95% confidence interval [CI]: 3.41 to 10.21) in the presence of metformin and 5.34 mL/min/1.73m2 (95% CI: 2.98 to 7.70) in its absence. The incidence of contrast-induced nephropathy was not affected by concurrent metformin, as shown by a (between-groups) standardized mean difference of 0.0007 (95% CI: -0.1007 to 0.1022).Conclusion: Concurrent metformin during percutaneous coronary interventions in patients with relatively preserved renal function is safe, without added risk of lactic acidosis or contrast-induced nephropathy. Thus, emergency revascularization in the context of acute coronary syndromes should not be deferred. More data from clinical trials in patients with severe renal disease are needed.

Abstract #1175554: Unmasking Diabetic Ketoacidosis in a Patient with Metformin Associated Lactic Acidosis

Lactic Acidosis is a very rare, dangerous side effect associated with metformin use. The incidence of Metformin-associated Lactic Acidosis (MALA) ranges between 3.3 to 4.7/100,000 patient-years. It carries a mortality rate of around 30%. We present a unique case of severe lactic acidosis in a type 2 diabetic patient presenting as MALA with diabetic ketoacidosis.

114-LB: Metformin-Associated Lactic Acidosis Risk Assessment in Veterans on Continuous Oxygen Therapy

Metformin is the most prescribed oral medication for type 2 diabetes in the US due to its low cost, efficacy in reducing insulin resistance, and overall safety profile. However, literature shows that metformin can cause a rare but serious side effect of lactic acidosis (LA) with an incidence of 0.03-0.06 per 1000 patients. Persons requiring continuous oxygen therapy (COT) may be at risk for LA associated with hypoxia and decreased tissue perfusion, but the risk of metformin associated lactic acidosis (MALA) in persons requiring COT is unclear. Due to lack of evidence, some clinicians may empirically discontinue metformin in patients on COT, compromising glycemic stability. The objective of this drug utilization evaluation was to determine the frequency of metformin use and incidence of MALA in patients receiving COT. A retrospective review was conducted at a large regional Veterans Affairs Medical Center for patients with active prescriptions of metformin and supplemental oxygen therapy from 4/2017-4/2020. Of 578 unique patients identified, manual medical-record review was conducted for 6 patients who had serum lactate levels &amp;gt;4 mmol/L while using concomitant metformin and COT. All were white males with mean: age of 71, pH of 7.35, and eGFR of 56. No cases of LA or DKA were identified. In all cases, elevated lactate levels were attributed to advanced medical conditions including: COPD, sepsis, CHF, CKD, and liver disease. None had serum metformin levels drawn. In conclusion, the association of elevated serum lactate among persons using concomitant metformin and COT was low and occurred in persons with advanced medical conditions. It could not be determined if metformin use was a contributing factor without metformin levels. These findings confirm the importance of clinical judgement when prescribing and continuing metformin for persons with advanced underlying medical conditions. Further study with serum metformin levels may help to better characterize the risk of MALA for persons on COT. Disclosure S. J. Lutz-mccain: None. B. E. Desanzo: None. B. Herk: None. M. Mclinden: None. M. M. Dinardo: None. R. Codario: None.

A Rare Case of Metformin Associated Lactic Acidosis in a Type 2 Diabetic Patient With No Known Contraindications for Metformin Prescription - a Diagnostic Conundrum!

Introduction: Metformin is a biguanide drug primarily inhibits hepatic gluconeogenesis and improves insulin sensitivity. Lactic acidosis is a rare complication of metformin. The incidence of Metformin-associated lactic acidosis (MALA) is 6.3 per 100,000 patient-years. Metformin raises lactate levels by inhibiting the conversion of lactate and pyruvate into glucose, shunting towards anaerobic glycolysis. Although, MALA is a reported side effect, metformin is still identified as the drug of choice for Type 2 DM. Here we present a case of MALA in a Type 2 Diabetic patient to shed light on this controversial dilemma. Case Presentation: A 56-year-old African-American male with Type 2 DM and diabetic retinopathy presented after a fall and generalized weakness. Upon arrival, his blood sugar was 22 mg/dL. Patient was vitally stable with signs of dehydration. Home medications includes Metformin 1000 mg twice daily and Glipizide. Laboratory results showed an anion gap metabolic acidosis of 18 mmol/L, Lactic acid was 6.5 mmol/L with repeat of 7.6 mmol/L. Creatinine was 6.0 mg/dL with a BUN of 89 mg/dL. Baseline creatinine from 1 year prior was 1.3–1.5 mg/dL with GFR of 52 mL/min. Hemoglobin A1c was 5.9%. Sodium bicarbonate infusion in 5% dextrose in water. The patient clinically improved with closure of the anion gap and resolution of the metabolic acidosis. Metformin level was 10 mcg/mL. He was discharged on basal insulin and discontinued Metformin and Glipizide. Discussion: Metformin is the first line treatment of Type 2 DM due to its safety. The most common adverse events of Metformin include nausea, bloating, and diarrhea. MALA is a rare, yet serious side effect with a reported mortality of 45%. Higher mortality was associated with increased age, lower arterial pH, and need for mechanical ventilation and vasopressor medicationsThe following criteria should raise concern for MALA in patients with history of Metformin use; elevated lactate level, high anion gap, severe acidosis, low serum bicarbonate level and a history of renal insufficiency. Our patient met the above criteria. The treatment approach for MALA includes adequate supportive measures and correction of acidosis with the acceleration of lactic acid metabolism. Ultimately, if there is no improvement with the aforementioned strategies, then the next step is elimination of the offending agent by renal excretion or dialysis. Fortunately our patient improved with intravenous hydration and did not require advanced intervention. This case highlights the importance of the early recognition of MALA in a patient with unexplained anion gap acidosis and history of Metformin use as even with no risk factors, an episode of gastroenteritis can be enough to impair renal function which increases the risk of MALA. More importantly, it is crucial to educate patients to withhold Metformin in the setting of acute illness and volume contraction to prevent MALA.

Monitoring Patients on Metformin: Recent Changes and Rationales.

Objective: The Food and Drug Administration recently updated metformin prescribing recommendations for patients with diabetes and renal disease. The American Diabetes Association as well as the American Association of Clinical Endocrinologists and American Clinical Endocrinologists also recommend periodic monitoring of vitamin B12 levels for patients using metformin. A review of the literature was conducted to assess data to evaluate the recent updates to metformin usage and provide rationales for these recommendations. Data Sources: PubMed MESH terms "Diabetes Mellitus, Type 2" and "Renal Insufficiency, Chronic" and "Metformin" were searched with an English limitation from 1990 to May 2017. A MEDLINE search was conducted using the terms "metformin" and "renal disease" from 1990 to May 2017. A PubMed search was conducted using the MESH terms "vitamin b12 deficiency" and "metformin" from 1970 to May 2017. A MEDLINE search was conducted using terms "metformin" and "vitamin B12 deficiency" with an English limitation from 1970 to May 2017. Study Selection and Data Extraction: Retrospective and prospective clinical trials, meta-analyses, and systematic reviews were considered for inclusion. Citations from identified articles were also reviewed for inclusion. Data Synthesis: The incidence of metformin-associated lactic acidosis is minimal. Data indicate metformin-treated patients with an estimated glomerular filtration rate above 30 mL/min/1.73 m2 have a reduction in mortality. Additionally, data suggest metformin may lead to vitamin B12 deficiency. Conclusion: Data support recommendations for metformin use in patients with diabetes and renal insufficiency with an estimated glomerular filtration rate above 30 mL/min/1.73 m2. Data also suggest that baseline and periodic testing of vitamin B12 levels are warranted and supported by clinical guidelines due to the risk of vitamin B12 deficiency in metformin-treated patients.

Metformin Use in Type 2 Diabetes Mellitus Tuberculosis Co-infection and the Risk of Lactic Acidosis: A Case Risk-Study

Metformin (MET) has possibilities to be utilized as an adjunct of TB therapy in controlling the growth of Mycobacterium tuberculosis (Mtb). MET enhances the production of mitochondrial reactive oxygen species and facilitates phagosome-lysosome fusion, those mechanism are important in Mtb elimination. Moreover, MET associated lactic acidosis (MALA) needs to be considered and the incidence of MALA in patients with type 2 DM-TB co-infection remains unknown. This result contributes much to our understanding about the clinical effect of MET use in type 2 DM-TB co-infection. An observational clinical study was done in type 2 DM newly TB co-infection outpatients at Surabaya Paru Hospital. Patients were divided into two groups. First group was MET group, whom was given MET accompanying insulin and TB treatment regimens, the golden standard therapy of DM-TB co-infection. MET therapy was given for at least 2 months. Second group was non MET group, were given insulin and TB treatment regimens. The lactate levels in both group were measured after 2 months. From 42 participants, there was no case of lactic acidosis during this study period. Data was normal distribution, thus we continued analysis the difference using paired t-test with 95% confidence. There was no difference in lactate levels (p=0.396) after MET therapy compared to non MET group. In this study, there is no evidence that MET therapy is induced lactic acidosis event nor increased of lactate blood level. Thus we concluded that MET use in type 2 DM-TB co-infection not induced lactic acidosis.

Metformin associated lactic acidosis in Auckland City Hospital 2005 to 2009.

To determine the incidence, clinical characteristics and outcomes of patients with metformin associated lactic acidosis (MALA). Auckland City Hospital drains a population of just over 400000 people. All cases presenting with metabolic acidosis between July 2005 and July 2009 were identified using clinical coding. A retrospective case notes review identified patients with MALA. Prescribing data for metformin was obtained from the national pharmaceutical prescribing scheme. There were 42 cases of metabolic lactic acidosis over 1718000 patient years. There were 51000 patient years of metformin prescribed to patients over the study period. There were thirty two cases of lactic acidosis due to sepsis, seven in patients treated with metformin. Ten cases of MALA were identified. The incidence of MALA was estimated at 19.46 per 100000 patient year exposure to metformin. The relative risk of lactic acidosis in patients on metformin was 13.53 (95%CI: 7.88-21.66) compared to the general population. The mean age of patients with MALA was 63 years, range 40-83 years. A baseline estimated glomerular filtration rate was obtained in all patients and ranged from 23-130 mL/min per 1.73 m(2). Only two patients had chronic kidney disease G4. Three patients required treatment with haemodialysis. Two patients died. Lactic acidosis is an uncommon but significant complication of use of metformin which carries a high risk of morbidity.

Adverse event notifications implicating metformin with lactic acidosis in Australia

ObjectiveTo summarise the reported lactic acidosis cases associated with metformin from the Australian Therapeutic Goods Administration (TGA) and estimate the incidence of metformin-associated lactic acidosis (MALA) in Australia. MethodAll “lactic acidosis” cases associated with metformin and reported to the TGA between January 1971 and October 2014 were included. Data extracted included patient demographics, medical history and co-existing conditions, metformin dosage and relevant pathology results. ResultA total of 152 cases of suspected MALA were included in this study. For 20 patients the outcome was unknown. There were 23 patients (n=132, 17.4%) reported as deceased. Plasma lactate levels were higher in non-survivors (p=0.02). Thirty-five patients (n=132, 26.5%) were reported to have at least one pre-existing contraindication to the use of metformin; this proportion was not different between patients who died or survived. Renal impairment was the most common contraindication. Approximately 75% of patients were reported to have at least one clinical condition which might cause acidosis. Metformin dosage, plasma lactate and serum creatinine were not correlated. Based on the cases reported to the TGA, the incidence of MALA in Australia was estimated to be 2.3 (95% CI, 1.5–3.1) cases per 100,000 patient–years between 1997 and 2011. ConclusionPre-existing clinical conditions, such as renal impairment, and acute illnesses associated with lactic acidosis were frequently reported in the cases of MALA. The estimated incidence of MALA was lower than in most previous studies in other countries, probably due to the nature of spontaneous reports to the TGA.

Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements

The reported incidence of metformin associated lactic acidosis (MALA) in type 2 diabetes mellitus (DM) is 3-9 cases per 100,000 patient-years. In clinical practice, 22-94% of patients using metformin have contraindications to metformin, so the incidence of MALA may be higher than reported. To estimate the incidence of MALA in type 2 DM patients by means of metformin serum concentration measurements and investigate the correlation of metformin serum concentration with the clinical outcome of MALA. MALA cases were identified by reviewing the medical records of patients with metformin serum concentrations measured between January 2000 and October 2008. MALA was defined as arterial pH <7·35 and lactate concentration >5·0 mmol/L in patients using metformin. The incidence of MALA was calculated from the number of cases and the at risk population. The correlation coefficient between the metformin and lactate concentration was calculated by linear regression. The relationship between metformin serum concentration, lactate concentration and outcome was examined by calculating the mean metformin and lactate concentration in patients who survived and those who died. The Student's t-test was used to compare groups. In 29 patients metformin serum concentration was measured, 16 had MALA. Eleven of the 16 MALA cases (69%) had risk factors for lactic acidosis in their medical history, 13 cases (81%) had renal failure on admission. The incidence of MALA was estimated at 47 per 100,000 patient-years, this is 5-16 times higher than previously reported. This may be explained by the use of metformin in the presence of risk factors for lactic acidosis. Survivors had a higher metformin serum concentration (18·9 mg/L) than non-survivors (2·9 mg/L, P = 0·006) which can be explained by less severe underlying disease in patients who survived MALA, rather than an effect of metformin itself. The incidence of MALA estimated from metformin serum concentration measurements in type 2 DM patients is 5-16 times higher than reported in literature. MALA is probably caused by the frequent use of metformin in the presence of risk factors for lactic acidosis. Metformin serum concentration measurements may aid in the timely diagnosis and therapy of MALA. The outcome of MALA is determined by the severity of the underlying disease, rather than by metformin itself.

Metformin Use in Patients With Diabetes and Heart Failure: Cause for Concern?

Patients with type 2 diabetes are 2.5 times more likely to develop heart failure than those without diabetes,1 and > 30% of patients with heart failure have concurrent diabetes.2 Biguanides, namely phenformin and metformin, have been used for the treatment of diabetes for decades. In certain clinical situations, however, the use of biguanides can result in an accumulation of lactic acid, which may result in a rare condition known as acute lactic acidosis (ALA), which is fatal in ∼ 50% of cases.3,4 In most instances, the development of ALA arises secondary to conditions predisposing patients to hemodynamic compromise and overt tissue hypoxia, such as acute myocardial infarction (MI), acute uncompromised heart failure, or sepsis.5,6 Phenformin was removed from the market in 1976 because of reports of both fatal and nonfatal phenformin-associated lactic acidosis (PALA).7 The incidence of PALA at the time was estimated to be between 40 and 64 cases per 100,000 patient-years, or four to six times that seen in patients with diabetes who were not on phenformin.8,9 Unlike phenformin, which is metabolized through the liver via hydroxylation, metformin is excreted unchanged in the urine.10 Therefore, metformin is less likely to inhibit hepatic lactate clearance and lead to ALA. The estimated incidence of metformin-associated lactic acidosis (MALA) in patients with diabetes is between 3 and 9 cases per 100,000 patient-years, roughly the same as that reported in patients with diabetes who are not taking a biguanide.4,7,11–13 Epidemiological data reveal that metformin is often used in patients with heart failure. Prospective and retrospective cohort studies have evaluated health care databases of hospitalized and outpatient diabetic populations to determine metformin usage in patients with concurrent International Classification of Diseases-9 (ICD-9) codes …

Metformin and antihypertensive therapy with drugs blocking the renin angiotensin system, a cause of concern?

The burden of diabetes mellitus type 2 (DM2) is increasing worldwide. The combination of DM2 and hypertension (HT) is frequently encountered. Concurrent use of drugs blocking the renin angiotensin system (angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB)) and metformin have become frequent in this group of patients. That combination can become life-threatening under certain circumstances. We present 5 patients with DM2 and HT who developed severe metformin-associated lactic acidosis in a setting with acute renal failure, precipitated by dehydration and aggravated by the use of ACEI or ARB. None of the patients had reduced renal function before the acute illness. They were admitted to the hospital in critical condition with severe metabolic acidosis (pH 6.60 6.94), high S-lactate (14 - 23 mmol/l) and S-creatinine 796 1,621 micromol/l. They were all hypothermic and 3 were hypoglycemic. All developed circulatory and respiratory collapse. They were treated with either intermittent bicarbonate hemodialysis (HD) or with continuous venovenous hemodiafiltration (CVVHDF) and bicarbonate buffering. All patients recovered without renal sequela. We believe that the incidence of metformin-associated lactic acidosis in Norway may become more frequent due to increased use of metformin and drugs blocking the renin angiotensin system. The awareness of lactic acidosis as a complication to the use ofmetformin in predisposed individuals is important. General advice should be given to patients regarding reduction of dosage or withdrawal of the drugs during acute intercurrent illness with dehydration. Early diagnosis and treatment of metformin-associated lactic acidosis are crucial for the patient outcome. Hemodialysis can be life-saving and should be started without delay.

Acidose lactique et metformine

Objective The aims of this review are to precise the pathophysiological mechanisms leading to biguanide-associated lactic acidosis, to give elements of diagnosis, and to underline the precautionary conditions for prescribing these drugs by an improvement in physicians and patient's education. Data sources A PubMed ® database research in English and French language reports published until December 2005. The keywords were: lactic acidosis, metformin, biguanide, diabetes mellitus. Data extraction Data in selected articles were reviewed, clinical and basic science research relevant informations were extracted. Data synthesis Metformin which is an oral antidiabetic agent, is the only one biguanide available in France. It acts by enhancing the sensitivity to insulin by a decrease in the hepatic glucose production and an increase in its peripheral use. In term of glycemic control, it has the same efficiency than the other hypoglycemic agents. It represents the treatment of choice for overweight type 2 diabetic patients because of its beneficial effects on the weight loss and on the cardiovascular complications. The incidence of metformin-associated lactic acidosis is very low when contra-indications and appropriate rules for prescribing this drug are respected. The relationship between metformin and lactic acidosis remains largely controversial. In practical, we can distinguish three situations which have different prognosis. In the first case, metformin seems to be responsible for lactic acidosis because of self-poisoning or accidental overdose, and prognosis is good. In the second case, the association between metformin and lactic acidosis is coincidental rather than causal, and may be induced by an underlying organ failure. In the last case there is a cause of lactic acidosis which is worsened by a precipitating factor leading to metformin accumulation. The 2 latter situations are very severe as mortality rate is about 50%. Symptomatic treatments and renal replacement therapy which allows metformin removal are the curative treatment. Prevention is essential. It requires the respect of metformin contraindications and a better education of physicians and patients for a safe prescription. Conclusion Due to its beneficial effects, metformin is the gold standard treatment for overweight type 2 diabetic patients. The essential precautionary conditions for prescribing metformin as well as the respect of its contra-indications permit largely to prevent lactic acidosis. This complication is serious when it is associated with intercurrent illnesses and metformin accumulation. The curative treatment is based on renal replacement therapy. Prevention only rests on the respect of the contra-indications. Education of physicians and patients concerning the rules of prescription remains essential.

Metformin‐associated lactic acidosis in patients with renal impairment solely due to drug accumulation?

We suspect that the life-threatening complication of metformin-associated lactic acidosis, solely due to drug accumulation following renal impairment, occurs more frequently than that previously reported and is not necessarily associated with other predisposing factors for lactic acidosis. During a period of 13 months, at a tertiary referral centre, the incidence of lactic acidosis of any aetiology was 12.8% [67 of 524 total intensive care unit (ICU) admissions]. Metformin-associated lactic acidosis solely as the result of drug accumulation was diagnosed in 6% of all the patients suffering from lactic acidosis (4 of 67 patients). These patients presented with severe circulatory shock due to lactic acidosis. We could not identify any predisposing factor for lactic acidosis other than renal impairment. Intercurrent deterioration of diabetic nephropathy was suspected to be responsible for the accumulation of metformin followed by lactic acidosis, finally resulting in multiorgan failure. The diagnosis was supported by extensively elevated serum levels of metformin. Two patients died during ICU treatment. Our data indicate that the incidence of metformin-associated lactic acidosis solely due to metformin accumulation is possible and underestimated. Symptoms of metformin-associated lactic acidosis are unspecific and physicians should be aware that metformin, if prescribed in patients with renal impairment, can cause fatal lactic acidosis due to drug accumulation.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

Metformin is an oral anti-hyperglycemic agent used in the treatment of type 2 diabetes mellitus. The results of the UK Prospective Diabetes Study indicate that metformin treatment is associated with a reduction in total mortality compared to other anti-hyperglycemic treatments. Metformin, however, is thought to increase the risk of lactic acidosis, and is considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. To assess the incidence of fatal and nonfatal lactic acidosis with metformin use compared to placebo and other glucose-lowering treatments in patients with type 2 diabetes mellitus. A secondary objective was to evaluate the blood lactate levels for those on metformin treatment compared to placebo or non-metformin therapies. A search was performed of the Cochrane Controlled Trials Register and the Database of Abstracts of Reviews of Effectiveness (up to 4/2000), Medline (up to 11/2000), Embase (up to 11/2000), Oldmedline, and Reactions (up to 5/2000), in order to identify all studies of metformin treatment from 1966 to November 2000. The Cumulated Index Medicus was used to search relevant articles from 1959 to 1965. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Date of latest search: November 2000. Prospective trials in patients with type 2 diabetes that lasted longer than one month were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Observational cohort studies of metformin treatment lasting greater than one month were also included. Two reviewers independently selected trials to be included, assessed study quality and extracted data. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for placebo or other treatments. The upper limit for the true incidence of cases in the metformin and non-metformin groups were calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed effects model for continuous data. Pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35,619 patient-years of metformin use or in 30,002 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals the upper limit for the true incidence of metformin-associated lactic acidosis was 8.4 cases per 100,000 patient-years, and the upper limit for the true incidence of lactic acidosis in the non-metformin group was 9 cases per 100,000 patient-years. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to placebo or other non-biguanide therapies. The mean lactate levels were slightly lower for metformin treatment compared to phenformin (WMD -0.75 mmol/L, 95% CI -0.86 to -0.15). 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 if prescribed under the study conditions, taking into account contra-indications.

Metformin-associated lactic acidosis: a rare or very rare clinical entity?

Lactic acidosis is a well recognized complication of biguanide therapy which is potentially serious. Although the prevalence of metformin-associated lactic acidosis (MALA) is much lower than that associated with phenformin, it is still being reported sporadically which raises concerns for the practising clinicians. We review the currently available world-wide data of the prevalence of MALA, the risk factors for its development and the current practical guidelines on the use of metformin to minimize the risk of this potential hazard. An extensive literature search was conducted from both Medline and Ovid (1965-98) using the following keywords: 'Type 2 diabetes mellitus', 'oral hypoglycaemic drugs', 'biguanides', 'metformin-associated lactic acidosis' and 'renal impairment'. MALA was found to be a very rare clinical entity, being 20 times less common than phenformin-associated lactic acidosis. Amongst all the risk factors, renal impairment appears to be the major precipitating factor for the development of MALA in metformin-treated patients. We also found cases of MALA where no precipitating factors were identified and the underlying mechanism in these cases remains unclear. Practical recommendations of metformin use to minimize the risk of MALA have been listed based on previous reports. The low prevalence of MALA is comparable to the prevalence of sulphonylurea-induced hypoglycaemia. Metformin has many beneficial metabolic effects in the management of Type 2 diabetes mellitus. Provided that the recommended guidelines for metformin use are strictly adhered to, its widespread use would be safe and the incidence of MALA will be further reduced.