Metformin toxicity: A meta-summary of case reports

Abstract

BACKGROUND Metformin is arguably the most commonly prescribed oral hypoglycemic agent for the management of diabetes. Due to the lack of randomized control trials, most of the data pertaining to the clinical course, therapeutic interventions and outcomes of patients with metformin induced toxicity has come from case reports or series. AIM To analyse the symptomology, clinical interventions and outcomes of patients presenting with severe metformin toxicity by reviewing the published case reports and series. METHODS We performed a systematic search from PubMed, Science Direct, Reference Citation Analysis ( ) and Google Scholar databases using the terms “metformin” AND “toxicity” OR “overdose” OR “lactic acidosis” OR “hyperlactatemia”. The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported toxicity or overdose of metformin in adults, published in the English language. Data regarding baseline demographics, clinical presentation, therapeutic interventions, intensive care unit course and overall outcome were collected. RESULTS Two hundred forty-two individual cases were analysed, from 158 case reports and 26 case series, with a cumulative mortality of 19.8%. 214 (88.4%) patients were diabetics on metformin. 57 (23.6%) had acute ingestion, but a great majority (76.4%) were on metformin in therapeutic doses when they developed toxicity. Metformin associated lactic acidosis (MALA) was the most commonly reported adverse effect present in 224 (92.6%) patients. Most of the patients presented with gastrointestinal and neurological symptoms and a significant number of patients had severe metabolic acidosis and hyperlactatemia. The organ support used was renal replacement therapy (RRT) (68.6%), vaso-pressors (58.7%) and invasive mechanical ventilation (52.9%). A majority of patients (68.6%) received RRT for toxin removal, renal dysfunction and correction of MALA. Patients with lowest pH and highest serum lactate and metformin levels also had favourable outcomes with use of RRT. CONCLUSION Most of the reported cases were on therapeutic doses of metformin but developed toxicity after an acute deterioration in renal functions. These patients may develop severe lactic acidosis, leading to significant morbidity and need for organ support. Despite severe MALA and the need for multiple organ support, they may have good outcomes, especially when RRT is used. The dose of metformin, serum pH, lactate and metformin levels may indicate the severity of toxicity and the need for aggressive therapeutic measures but may not necessarily indicate poor outcomes.

Metformin toxicity in the intensive care unit: A case series and review of the literature

“…[ 23 ] Respectively, lower and higher mortality rates of 20% and 50% have also been reported. [ 14 24 ] Factors associated with mortality include a high Acute Physiology and Chronic Health Evaluation (APACHE) III score, shock as the reason for ICU admission, and possibly a high peak lactate level [ Table 2 ]. [ 20 23 ] Patients referred for shock had an increased risk for death compared to those referred for acute renal failure or suicide attempt.…”

“…[ 7 8 ] Once a toxic threshold has been exceeded, several organ systems may be affected [ Figure 1 ]. [ 2 9 10 11 12 13 14 ] The Federal Drug Agency has defined metformin toxicity as serum levels ≥ 5 μg/ml. [ 15 ] However, metformin levels are seldomly evaluated in clinical settings due to the nonavailability of rapid laboratory tests.…”

“…[ 16 17 ] Abnormal laboratory findings include elevated hepatic transaminases, creatinine, urea, and hypoglycemia. [ 13 14 17 18 ] Most striking is a profound metabolic acidosis refractory to intravenous (IV) fluids and vasopressors. Contrary to its portended poor prognosis and high mortality, the successful treatment of metformin toxicity can be achieved by early recognition and emergent hemodialysis (HD).…”

A Diagnostic Dilemma “Cured” by Dialysis: An Educational Case Report

“…A meta-summary of metformin toxicity case reports was recently performed, and 242 individual cases were analyzed. 6 Metformin-associated lactic acidosis (MALA) was the most commonly reported toxicity, present in 92.6% of patients. A majority (68.6%) required kidney replacement therapy for toxin removal and correction of MALA.…”

Fatal Metformin Poisoning: Adolescent Case Report

“…Metformin is a biguanide oral hypoglycemic agent used for Non-Insulin Dependent Diabetes Mellitus (NIDDM) [1]. It is arguably the most commonly prescribed oral hypoglycemic agent [2]. In the absence of overdose or intoxication, the side effects of metformin are usually minor, consisting of digestive disorders: dyspepsia, nausea, vomiting.…”