Metformin-associated Lactic Acidosis Research Articles

Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients.

Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m2 or better before restarting metformin.

#2589 Predictive value of serum lactate in ICU dialysis-dependent AKI patients

Abstract Background and Aims Hyperlactatemia is frequently observed in critically ill patients. It is often associated with unfavorable outcomes and serves as a strong predictor of mortality. Renal replacement therapy aims to mitigate lactate accumulation in this particular subgroup of patients, but the effectiveness of this therapy in reducing morbidity and mortality in acute kidney injury (AKI) associated lactic acidosis remains inconclusive. The aim of this retrospective study was to evaluate the predictive role of serum lactate in dialysis-dependent AKI patients stratified on three different underlying etiologies (septic shock, concomitant liver failure and metformin-associated lactic acidosis). Method A retrospective, single-center cohort analysis was conducted to examine patients with AKI who underwent hemodialysis in our ICU between 2022 and 2023 and had a serum lactate > 4 mmol/L. Patients were stratified according to underlying etiology: isolated septic shock with AKI, shock with concomitant AKI and fulminant liver failure (serum ammonia > 100 µmol/L), and AKI with metformin-associated lactic acidosis (MALA). We compared patients according to age and 3-day, 30-day, and 90-day mortality. Finally, we performed receiver-operating-curve (ROC) analysis to potential predictive power of serum lactate for 30-day mortality. Results The median age of our cohort of 63 patients was 67 (range 52 - 74) years, with a median lactate level of 12.9 (7.6 – 18.0) mmol/L. The 3-day, 30-day and 90-day mortality rate was 57%, 78%, and 83%, respectively. We observed that patients with concomitant liver failure were significantly younger (p = 0.004). Interestingly, while all groups have comparable 90-day mortality, patients with septic shock exhibit extremely high 3-day mortality (74%), compared to 35% and 25% for acute liver failure and metformin-associated shock. ROC curve analysis showed that serum lactate was highly predictive of 30-day mortality in group of AKI with concomitant fulminant liver dysfunction. On the contrary, in metformin-associated hyperlactatemia the level of serum lactate showed no such prediction. Conclusion Our retrospective analysis underscores the crucial importance of differentiating between various groups of patients (septic shock, concomitant liver failure and metformin-associated lactic acidosis) in patients with hyperlactatemia. In metformin-induced kidney failure, the level of lactate does not predict mortality, while in the cases of AKI with concurrent acute liver dysfunction our results are highly suggestive that dialysis may not be effective for severe lactacidosis. The findings contribute valuable insights for designing future prospective studies in this complex patient population.

Metformin-Associated Lactic Acidosis: Which Elimination Therapy to Use in Case of Haemodynamic Instability? A Retrospective Cohort Study

Introduction: Metformin, a commonly used oral antihyperglycemic drug, poses a rare risk related to the development of metformin-associated lactic acidosis (MALA). The Extracorporeal Treatments in Poisoning (EXTRIP) group recommended intermittent haemodialysis (IHD) as a primary elimination therapy in case of severe metformin poisoning. However, in haemodynamically unstable patients, our previous observations suggested that continuous venovenous haemofiltration (CVVH) might be more effective. This retrospective cohort study aimed to contribute evidence on the use of IHD and CVVH in patients with severe MALA, particularly in haemodynamically unstable patients. Methods: Data from January 2015 to December 2020 were collected from the Leuven University Hospital. Two separate search methods, based on hospital activity records and laboratory criteria, were used to identify patients with MALA. Patients diagnosed with MALA, receiving extracorporeal treatment within 24 h of admission, were included. Patients were categorized into the IHD and CVVH groups. Patient characteristics, treatment details, and outcomes were analysed. Results: Among 358,148 patient records, 35 MALA cases were identified. IHD was chosen as the initial elimination technique in 13 cases, whereas 22 patients were first commenced on CVVH. Patients treated with CVVH were sicker, had more comorbidities and had higher ventilation and vasopressor requirements. CVVH group had longer vasopressor use, longer ICU stays, and higher in-hospital mortality. Discussion: CVVH rather than IHD seems to be the preferred elimination technique in the more critically ill patients with MALA. Due to its retrospective design, this study failed to identify the superior elimination technique in terms of efficacy. Poorer outcomes in the CVVH group are likely attributed to the severity of illness rather than the inferiority of the elimination therapy. We acknowledge the diagnostic challenges regarding MALA. Using metformin assays could be beneficial in managing these patients. Conclusions: This study suggests clinicians’ preference for CVVH in severe cases of MALA with haemodynamic instability.

Methylene Blue in Metformin Intoxication: Not Just Rescue But Also Initial Treatment.

Metformin (MTF) is a widely used oral antidiabetic medication. Regardless the reason, high doses of MTF cause lactic acidosis as a result of its effects on mitochondrial ATP production and no-mediated vascular smooth muscle relaxation. Metformin-associated lactic acidosis can be life-threatening despite all treatments. Methylene blue (MB) has the potential to reverse the toxic effects of MTF through its effects on both the mitochondrial respiratory chain and nitric oxide production. The use of MB in MTF intoxication has only been reported in a limited number of cases. Herein, we present a 16-year-old female patient who attempted suicide by ingesting high doses of MTF. Supportive treatments, such as vasopressor, inotropic treatments, and sodium bicarbonate, were started in the patient who developed fluid-resistant hypotension after pediatric intensive care unit admission. Because of rising lactate levels, Continuous renal replacement therapy (CRRT) was started immediately. Despite all treatments, hypotension and hyperlactatemia persisted; MB was given as a rescue therapy. Noticeable hemodynamic improvement was observed within 30 minutes of initiating MB infusion, allowing a gradual decrease in the doses of inotropic infusions within the first hour of therapy. Patient's cardiovascular support was discontinued on the second day, and she was discharged on the fifth day. We speculate that, considering the mechanisms of MTF toxicity and the mechanisms of action of MB, it is suggested that early administration of MB, not only as a rescue treatment but as the initial approach to MTF poisoning in combination with other treatments, may result in improved outcomes.

GC–MS analysis of 4-hydroxyproline: elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients

Metformin (N,N-dimethylbiguanide), an inhibitor of gluconeogenesis and insulin sensitizer, is widely used for the treatment of type 2 diabetes. In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate ≥ 5 mM, pH < 7.35, and metformin concentration > 38.7 µM). Here, we report on the post-translational modification (PTM) of proline (Pro) to 4-hydroxyproline (OH-Pro) in metformin-associated lactic acidosis and in metformin-treated patients with Becker muscular dystrophy (BMD). Pro and OH-Pro were measured simultaneously by gas chromatography–mass spectrometry before, during, and after renal replacement therapy in a patient admitted to the intensive care unit (ICU) because of MALA. At admission to the ICU, plasma metformin concentration was 175 µM, with a corresponding lactate concentration of 20 mM and a blood pH of 7.1. Throughout ICU admission, the Pro concentration was lower compared to healthy controls. Renal excretion of OH-Pro was initially high and decreased over time. Moreover, during the first 12 h of ICU admission, OH-Pro seems to be renally secreted while thereafter, it was reabsorbed. Our results suggest that MALA is associated with hyper-hydroxyprolinuria due to elevated PTM of Pro to OH-Pro by prolyl-hydroxylase and/or inhibition of OH-Pro metabolism in the kidneys. In BMD patients, metformin, at the therapeutic dose of 3 × 500 mg per day for 6 weeks, increased the urinary excretion of OH-Pro suggesting elevation of Pro hydroxylation to OH-Pro. Our study suggests that metformin induces specifically the expression/activity of prolyl-hydroxylase in metformin intoxication and BMD.

Metformin-dolutegravir interaction leads to metformin-associated lactic acidosis: A case report

Metformin, a biguanide, is considered the standard first-line drug for managing type 2 diabetes mellitus (T2DM) patients owing to its safety profile. Despite having a highly safe profile, it is capable of causing serious adverse effects. Biguanides decrease gluconeogenesis from alanine, pyruvate, and lactate, which may result in lactic acidosis. The risk is high in patients with polypharmacy or comorbidities. This is a case of a 48-year-old Indian female with a known case of human immunodeficiency virus (HIV), T2DM, hypothyroidism, and hypertension who presented to the hospital with progressive right-sided weakness for the past 10 days along with transit loss of vision. The patient was diagnosed with multiple central nervous system tuberculomas, for which antitubercular treatment and dexamethasone were started. The patient was on a tenofovir, lamivudine, and dolutegravir regimen for HIV. The patient was started on metformin for sugar control, which led to metformin-associated lactic acidosis. A drug interaction between dolutegravir and metformin was attributed to this. The patient improved after metformin was replaced with glipizide, and lactate levels returned to normal. Lactic acidosis is a rare side effect of metformin. However, the risk of lactic acidosis is high when another drug interferes with metformin pharmacokinetics. Proper assessment and evaluation of potential drug–drug interactions is crucial to assure safe and effective therapy.

Renal manifestations of metformin-associated lactic acidosis; new findings

Renal manifestations of metformin-associated lactic acidosis; new findings

P-29 Metformin poisoning without lactic acidosis: Case report

Abstract Introduction Metformin is the most widely used oral antidiabetic, which belongs to the biguanide pharmacological group. Metformin-associated lactic acidosis (MALA) is a rare event with an incidence of approximately 19 cases per 100,000 patient-years. The risk of developing lactic acidosis, when taking metformin is enhanced by several factors such as: age &amp;gt; 65 years; concomitant diseases that have the ability to induce hypoxemia (chronic renal failure, congestive heart failure, cardiogenic shock, severe lung disease, sepsis, advanced liver disease, history of lactic acidosis); an excessive alcohol consumption; an administration of iodinated contrast agents. Clinical Case A 46-year-old man was urgently admitted with the following symptoms: drowsiness, repeated vomiting, lethargy, dizziness. The symptoms started after he administered outpatient and at own initiative 50 tablets of metformin, each tablet contains a dose of 500 mg (total dose 25g). Concomitant pathologies: diagnosed with Type 2 Diabetes for 8 years; Toxic liver cirrhosis, compensated Child-Pugh A (recently diagnosed); hypertension; CKD G3aA2 KDIGO. The patient's condition at admission was assessed as extremely serious, Glasgow scale - 11 points, mild hypertension, tachycardia, tachypnea. The paraclinical investigations revealed the presence of metabolic acidosis, but with lactate &amp;lt;5 mmol/l; the progressive renal dysfunction with creatinine values in the first 24 hours up to 1184 µmol/l, urea – 24.5 mmol/l; a severe hypoglycemia - 1.68 mmol/l; a moderate cytolytic syndrome; a cholestatic syndrome, an inflammatory and hepatoprive syndrome; coagulation disorders; a pancreatic dysfunction. In the context of the evident increase of urea and creatinine, the decision was made to initiate the intermittent hemodialysis, a total of 14 sessions were required during hospitalization. The particularity of this case is represented by the absence of lactic acidosis, despite metformin intoxication with altered neurological status, acute renal failure, developed due to chronic kidney disease, liver cirrhosis of toxic etiology and severe hypoglycemia. Conclusion Metformin should be administered with caution in patients with multiple comorbidities. Metformin intoxication can induce lactic acidosis with an increased risk of serious, potentially fatal adverse events. It is essential to identify metformin intoxication as early as possible, with prompt initiation of renal replacement measures and dynamic monitoring of biochemical parameters.

Analysis of Metformin-Associated Lactic Acidosis using the Japanese Adverse Drug Event Report Database

Analysis of Metformin-Associated Lactic Acidosis using the Japanese Adverse Drug Event Report Database

Metformin-Associated Lactic Acidosis Precipitated by an Acute Obstructing Ureteral Stone in a Patient with a Single Functioning Kidney

A 35-year-old male with type-2 diabetes mellitus and a history of insulin and metformin (2,000 mg/day) use presented to the emergency department (ED) with generalized weakness. Abdominal computed tomography (CT) performed 3 months prior to presentation showed a severely atrophic right kidney and a few tiny stones in the left kidney, with a serum level of creatinine of 1.14 mg/dL. At the ED, the patient’s blood pressure was 153/89 mmHg. Workup revealed acute kidney injury (creatinine, 11.97 mg/dL), high-anion-gap metabolic acidosis (pH, 6.93), and a blood lactic acid level &gt; 15 mmol/L. Based on the medication history, the patient was diagnosed with metformin-associated lactic acidosis. CT showed a left distal ureteral stone, measuring 6 mm in size, which resulted in hydroureteronephrosis. The patient was initially treated with continuous renal replacement therapy. Subsequently, left percutaneous nephrostomy was performed, which led to the return of the creatinine level to baseline, with complete resolution of lactic acidosis.

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.

Reversible acute blindness in suspected metformin-associated lactic acidosis: a case report

BackgroundMetformin is commonly used for the treatment of type 2 diabetes mellitus. Its multiple advantages include low risk of hypoglycemia, weight neutrality, low cost, and cardioprotective and anti-inflammatory effects. Renal insufficiency is one of the contraindications for its use. Inadvertent prescription in patients with renal insufficiency may lead to metformin-associated lactic acidosis, which brings a high risk of mortality. The early recognition and management of metformin-associated lactic acidosis are essential.Case reportWe present the case of a 58-year-old Hui woman with a history of type 2 diabetes mellitus with nephropathy and heart disease for which she was treated with metformin, insulin, and heart medications. She developed nausea, vomiting, anion gap metabolic acidosis due to hyperlactatemia, and acute kidney injury. She was hospitalized to receive intravenous hydration and correction of metabolic acidosis after she suddenly developed blindness. The diagnostic workup ruled out central causes and her symptoms resolved briefly after continuous venovenous hemodialysis was initiated, confirming the diagnosis of metformin-associated lactic acidosis.ConclusionsMetabolic disruption can cause acute blindness. Metabolic acidosis in a patient with a history of metformin intake should suggest the possibility of metformin-associated lactic acidosis, which must be treated immediately, without waiting for the results of other examinations, especially in patients with sudden blindness. Further study of reversible blindness-associated severe metabolic acidosis is needed.

Successful Treatment of a Rare Profound Lactic Acidosis and Anuric AKI due to Metformin-Associated Lactic Acidosis

Successful Treatment of a Rare Profound Lactic Acidosis and Anuric AKI due to Metformin-Associated Lactic Acidosis

An adolescent female with intentional ingestion of a large amount of metformin requiring extracorporeal membrane oxygenation and continuous renal replacement therapy

Acute overdose of metformin can show potentially fatal lactic acidosis. Management should be directed towards close monitoring of renal function and hemodynamics. Patients may require dialysis or extracorporeal membrane oxygenation in cases of hemodynamic instability. This case presents an adolescent with massive metformin ingestion estimated at 100 g leading to metformin-associated lactic acidosis and subsequent respiratory failure, cardiovascular collapse, and acute kidney injury. The complications were successfully managed with venoarterial extracorporeal membrane oxygenation, continuous renal replacement therapy, and mechanical ventilation.

Treatment of severe metformin-associated lactic acidosis with renal replacement therapy and tris-hydroxymethyl aminomethane: a case report

BackgroundType B lactic acidosis is a rare but serious side effect of metformin use. The risk of metformin-associated lactic acidosis is elevated in renal or liver impairment, heart failure and in metformin overdose. Metformin-associated lactic acidosis is treated with renal replacement therapy although this can be limited by metformin’s large volume of distribution and a patient’s hemodynamic instability. Tris-hydroxymethyl aminomethane is a buffer that rapidly equilibrates in liver cells and increases the intracellular pH of hepatocytes. Intracellular alkalosis increases lactate uptake by the liver and can promote gluconeogenesis which results in increased lactate metabolism and decreased lactate production. Unlike intravenous bicarbonate which can worsen acidosis due to carbon dioxide retention and hypocalcemia, tris-hydroxymethyl aminomethane does not generate large amounts of carbon dioxide and can improve cardiac contractility in experimental models.Case presentationWe present a case of a 43-year-old African American male who intentionally ingested 480,000 g of metformin. He developed severe metformin-associated lactic acidosis that was refractory to 21 hours of high flux hemodialysis. This was followed by an additional 12 hours of high flux hemodialysis augmented by continuous intravenous infusion of tris-hydroxymethyl aminomethane. After initiating tris-hydroxymethyl aminomethane, the patient had rapid reversal of lactic acidosis and was weaned off vasopressors and mechanical ventilation.ConclusionsWhile metformin-associated lactic acidosis can be treated with renal replacement therapy, severe cases of lactic acidosis may not be amenable to renal replacement therapy alone. Through its unique buffer mechanisms, tris-hydroxymethyl aminomethane can be used in conjunction with dialysis to rapidly improve acidosis associated with metformin.

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

THU382 It’s Not What It Seems - Metformin Induced Severe Lactic Acidosis Mimicking Euglycemic Diabetic Ketoacidosis

Abstract Disclosure: M. Shaukat: None. R. Memon: None. M. Mack: None. E. Galarza: None. R. Saeed: None. Diabetic Ketoacidosis (DKA) is a life-threatening complication and, occasionally, the initial presentation of Diabetes Mellitus (DM). DKA can rarely present without elevated blood glucose levels, known as Euglycemic DKA, now typically associated with SGLT-2 inhibitors. Metformin is known to cause lactic acidosis but has not been reliably associated with euglycemic DKA. We present a case of metformin-associated lactic acidosis with renal failure and ketosis mimicking euglycemic DKA. Case: 82-year-old female with a history of DM type 2 on metformin and hypertension presented to the Emergency Department (ED) with complaints of presyncope, vomiting and generalized weakness for two weeks. In the ED, her temp. was 90.3 F and BP was 66/28 mmHg. Her labs revealed a potassium of 5.4mmol/L, bicarbonate 5 mmol/L, Creatinine 3.68 mg/dL (baseline 0.7mg/dL), Anion gap (AG) 45mmol/L, Lactate 25.1 mmol/L and Beta-hydroxybutyrate of 21.4 mg/dL. CT Scan of the chest and abdomen showed a 2 cm liver mass and pancreatitis. She was taken to the ICU and started on antibiotics, IV fluids, and vasopressors. The following day, her lactate was 13.5mg/dL, AG was 37mmol/L and Beta-hydroxybutyrate increased to 53.5mg/dL. Her blood sugars remained between 140-180mg/dL and her hemoglobin A1c was in the prediabetic range at 6.1%. She was thought to be in metformin induced euglycemic diabetic ketoacidosis and was started on an insulin drip with 5% Dextrose and 0.45% Normal Saline. Nephrology was consulted and she underwent hemodialysis for metformin toxicity. She remained on the insulin drip for 48 hours after which she was successfully weaned off. She currently remains off on any antidiabetic medication and is doing well. Discussion: DKA is a life-threatening complication of DM that presents as hyperglycemia, ketonemia, and AGMA. Euglycemic DKA is distinguished by blood glucose levels less than 250mg/dL and is usually seen with pregnancy, fasting states and use of SGLT-2 inhibitors. Previous cases of metformin-associated lactic acidosis (MALA) and concurrent euglycemic DKA have been reported, out of which several patients were concurrently on SGLT-2 inhibitors. After a thorough literature review, we were unable to determine a causal mechanism linking metformin and euglycemic DKA. In the reported cases, we believe that renal failure from various causes precipitated MALA due to decrease metformin clearance, with ketosis caused by starvation and exacerbated by metformin-induced inhibition of hepatic gluconeogenesis, further aggravated by an increase in stress hormones resulting in increased insulin resistance and ultimately leading to the development of the severe ketoacidosis. Even though this phenomenon has previously been referred to as “Metformin-induced euglycemic DKA”, we believe that this is more akin to a mimic, rather than true DKA. Presentation: Thursday, June 15, 2023

Unusual case of concurrent metformin-associated lactic acidosis and euglycaemic ketoacidosis

Metformin-associated lactic acidosis (MALA) and euglycaemic diabetic ketoacidosis (EKA) are both life-threatening endocrine emergencies. MALA is a well-documented complication of anti-glycaemic therapy in diabetics while EKA is an increasingly recognized disease entity with the advent of use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors. However, the occurrence of concurrent metformin-associated lactic acidosis and euglycaemic ketoacidosis (MALKA) is uncommon and rarely reported in the literature. We report an unusual case of MALKA, in a 74-year-old gentleman with no previous history of chronic kidney disease and SGLT-2 inhibitor use, who presented with altered mental status, acute renal failure and profound high anion-gap metabolic acidosis (HAGMA) with lactaemia, ketonaemia and normoglycaemia (pH 6.965, bicarbonate 3.1, creatinine 522, glucose 6.6, lactate 17.5, ketones &gt;8). The patient was initiated on intravenous insulin infusion with dextrose-containing drip and continuous renal replacement therapy (CRRT) in the intensive care unit (ICU). The patient had a prolonged hospital stay but was eventually discharged with a normalised renal function without need for long-term dialysis. The parallel occurrence of MALA and EKA suggest a metformin-associated inhibition of gluconeogenesis. This case highlights the importance of early recognition and investigation of concurrent diabetic ketoacidosis in the presence of MALA and vice versa as MALKA benefits from both prompt institution of parenteral glucose therapy and insulin infusion and consideration of initiation of haemodialysis.

Calcium-Citrate Anticoagulation during Continuous Renal Replacement Therapy in Patients with Metformin Intoxication: A Case Series, Mathematical Estimation of Citrate Accumulation, and Literature Review

Plain Language SummaryMetformin intoxication is a potentially life-threatening condition characterized by severe metabolic acidosis that could require intensive care unit admission and renal replacement therapy (RRT) for metformin removal. According to current guidelines, a citrate solution is commonly administered to generate regional anticoagulation in RRT due to its effect on chelating ionized calcium, an essential element of the coagulation pathway. Citrate metabolism can be impaired during metformin intoxication, and its administration could lead to accumulation worsening the metabolic acidosis. Citrate is not routinely measured, and its accumulation is clinically diagnosed by the ratio between total and ionized plasma calcium concentration (T/I calcium ratio) >2.5 or estimating the presence of unmeasured anions (UA), calculating the strong ion gap (SIG), i.e., the difference between the strong anions and cation, and the concentration of bicarbonate, dissociated albumin, and phosphates. We compared our results obtained from a case series of three patients with a theoretical model of citrate accumulation. Finally, we reviewed the literature to unveil clinical practice in this scenario. Our results support that diluted citrate can be safely used for RRT in patients with metformin toxicity, and the SIG is a valuable tool to estimate the presence of UA and can be used to detect and monitor citrate accumulation in this context.

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.