The Role of Metformin in Metformin-Associated Lactic Acidosis (MALA): Case Series and Formulation of a Model of Pathogenesis

Duong, Janna K; Furlong, Timothy J.; Roberts, Darren M.; Graham, Garry G.; Greenfield, Jerry R.; Williams, Kenneth M.; Day, Richard O.

doi:10.1007/s40264-013-0038-6

Cited by 77 publications

(101 citation statements)

References 59 publications

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“…Some authors argue the relevance between high concentrations of metformin and lactic acidosis, because supratherapeutic plasma concentrations of metformin have frequently been found in patients with lactic acidosis during metformin use, and high metformin concentrations have been shown to increase plasma lactate levels in rats. 3,10,33) However, both chronic renal insufficiency and a high dose of metformin remain controversial as risk factors for lactic acidosis. The risk of lactic acidosis or elevated lactate levels was reported to be significantly increased in patients with mild to moderate renal insufficiency.…”

Section: Discussionmentioning

confidence: 99%

“…35), and electrolyte disturbances. 5,[7][8][9][10] Estimated rates of lactic acidosis incidence in metformin users range from 1 to 47 cases per 100000 patient-years. 11,12) Reported predisposing factors include acute kidney injury, history of lactic acidosis, hypovolemia, seizure, liver disease, alcohol abuse, acute heart failure, myocardial infarction, and shock.…”

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confidence: 99%

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Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin

Yokoyama

Tsuji

Hiraoka

et al. 2016

Biological & Pharmaceutical Bulletin

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Metformin is a biguanaide antidiabetic drug used worldwide, and its effectiveness and benefits have already been established. However, the safety of high doses of metformin in Japanese patients, especially in elderly patients with a decreased renal function, remains unclear. Among the side effects of metformin, lactate acidosis is the most problematic due to a high mortality rate. Therefore, we assessed plasma lactate levels in metformin-treated patients to identify independent risk factors for hyperlactemia. 290 outpatients receiving various doses of metformin at our hospital were enrolled between March and July 2014. Serum electrolytes, Cre (creatinine), BUN (blood urea nitrogen), UA (uric acid), HbA1c (hemoglobin A1c), and lactate levels were investigated. Lactate levels did not significantly differ between the elderly (≥75 years) and non-elderly (<75 years) groups. Patients in the elderly group had a significantly lower daily metformin dose and estimated glomerular filtration rate (eGFR), compared with the non-elderly group (both p<0.005). Between with and without hyperlactemia groups, no significant differences were observed in either Cre or age. On the other hand, patients with hyperlactemia had a significantly higher dose of metformin than those without hyperlactemia (p<0.05). In this study, we found that old age and mildly impaired kidney function were not associated with increased lactate levels, and that a higher dose of metformin may be an independent risk factor for elevated lactate levels in Japanese patients.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin

Yokoyama

Tsuji

Hiraoka

et al. 2016

Biological & Pharmaceutical Bulletin

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“…characterized by an elevated blood lactate concentration (.5 mmol/L), decreased blood pH (,7.35) and electrolyte disturbances with an increased anion gap (1,(6)(7)(8)(9). Estimated rates of lactic acidosis incidence during metformin use range from 1 to 47 cases per 100,000 patientyears (10,11).…”

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confidence: 99%

Risk of Lactic Acidosis or Elevated Lactate Concentrations in Metformin Users With Renal Impairment: A Population-Based Cohort Study

et al. 2014

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OBJECTIVEThe objective of this study was to determine whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis or elevated lactate concentrations compared with users of a noninsulin antidiabetic drug (NIAD) who had never used metformin. RESEARCH DESIGN AND METHODSA cohort of 223,968 metformin users and 34,571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD). The primary outcome was defined as either a CPRD READ code lactic acidosis or a record of a plasma lactate concentration >5 mmol/L. The associations between renal impairment, dose of metformin, and the risk of lactic acidosis or elevated lactate concentrations were determined with time-dependent Cox models and expressed as hazard ratios (HRs). RESULTSThe crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100,000 person-years (vs. 2.2 per 100,000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function <60 mL/min/1.73 m 2 (adjusted HR 6.37 [95% CI 1.48-27.5]). The increased risk among patients with impaired renal function was further increased in users of ‡730 g of metformin in the preceding year (adjusted HR 11.8 [95% CI 2.27-61.5]) and in users of a recent high daily dose (>2 g) of metformin (adjusted HR 13.0 [95% CI 2.36-72.0]). CONCLUSIONSOur study is consistent with current recommendations that the renal function of metformin users should be adequately monitored and that the dose of metformin should be adjusted, if necessary, if renal function falls below 60 mL/min/1.73 m 2 .There is good evidence that metformin reduces the long-term incidence of macrovascular complications in type 2 diabetes mellitus, especially among overweight patients (1-3). In contrast to alternative oral noninsulin antidiabetic drugs (NIADs) and insulin, metformin is not associated with a risk of hypoglycemia (3-5). The most serious adverse event that has been observed during metformin use is lactic acidosis, which is

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“…21 Observational studies suggest that it may be more common during intercurrent illness, particularly when there is vomiting, diarrhoea and acute kidney injury. 22 Metformin is unlikely to induce hypoglycaemia but it can aggravate symptoms of nausea, vomiting and diarrhoea, which may increase the risk of renal dysfunction. Vomiting and diarrhoea can be early signs of lactic acidosis and may prompt further investigation.…”

Section: Metforminmentioning

confidence: 99%

“…Vomiting and diarrhoea can be early signs of lactic acidosis and may prompt further investigation. 22 …”

Section: Metforminmentioning

confidence: 99%

Medication management on sick days

Lea‐Henry¹,

Baird-Gunning²,

Petzel³

et al. 2017

Aust Prescr

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The Role of Metformin in Metformin-Associated Lactic Acidosis (MALA): Case Series and Formulation of a Model of Pathogenesis

Cited by 77 publications

References 59 publications

Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin

Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin

Risk of Lactic Acidosis or Elevated Lactate Concentrations in Metformin Users With Renal Impairment: A Population-Based Cohort Study

Medication management on sick days

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