Lactic Acidosis in Patients with Diabetes Treated with Metformin

Misbin, Robert I.; Green, L; Stadel, Bruce V.; Gueriguian, John L.; Gubbi, Ananda; Fleming, G. Alexander

doi:10.1056/nejm199801223380415

Cited by 372 publications

(260 citation statements)

References 3 publications

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“…First, although extremely rare, with one estimate of reported incidence of 5 cases per 100,000 patients/year24, Metformin may carry a risk of lactic acidosis 25. Importantly, these episodes occurred in patients who were already at increased risk for lactic acidosis, making the role of Metformin as a precipitant less clear 24.…”

Section: Discussionmentioning

confidence: 99%

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

McCormick

Farmer

Perlman

et al. 2017

Ann Clin Transl Neurol

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ObjectiveFriedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age‐specific prevalence of FA‐associated DM and its impact on neurologic outcomes.Research Design and MethodsParticipants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes.ResultsMean age of participants was 30.1 years (SD 15.3, range: 7–82), 50% were female, and 94% were non‐Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA‐associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: −0.56–0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals.Conclusions DM‐associated FA has an independent adverse impact on well‐being in affected individuals, particularly at younger ages. In future, evidence‐based approaches for identification and management of FA‐related DM may improve both health and function.

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Section: Discussionmentioning

confidence: 99%

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

McCormick

Farmer

Perlman

et al. 2017

Ann Clin Transl Neurol

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“…Poisson statistics reported 5.1 cases per 100,000 patient-years [59,60]. There is some evidence that high doses of metformin lead to MALA, especially in patients with impaired kidney function [61,62]. No large, prospective, randomized trials of metformin have been carried out in children.…”

Section: Pathophysiologymentioning

confidence: 99%

Drug-induced acid-base disorders

et al. 2014

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The incidence of acid-base disorders (ABDs) is high, especially in hospitalized patients. ABDs are often indicators for severe systemic disorders. In everyday clinical practice, analysis of ABDs must be performed in a standardized manner. Highly sensitive diagnostic tools to distinguish the various ABDs include the anion gap and the serum osmolar gap. Drug-induced ABDs can be classified into five different categories in terms of their pathophysiology: (1) metabolic acidosis caused by acid overload, which may occur through accumulation of acids by endogenous (e.g., lactic acidosis by biguanides, propofol-related syndrome) or exogenous (e.g., glycol-dependant drugs, such as diazepam or salicylates) mechanisms or by decreased renal acid excretion (e.g., distal renal tubular acidosis by amphotericin B, nonsteroidal antiinflammatory drugs, vitamin D); (2) base loss: proximal renal tubular acidosis by drugs (e.g., ifosfamide, aminoglycosides, carbonic anhydrase inhibitors, antiretrovirals, oxaliplatin or cisplatin) in the context of Fanconi syndrome; (3) alkalosis resulting from acid and/or chloride loss by renal (e.g., diuretics, penicillins, aminoglycosides) or extrarenal (e.g., laxative drugs) mechanisms; (4) exogenous bicarbonate loads: milk-alkali syndrome, overshoot alkalosis after bicarbonate therapy or citrate administration; and (5) respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment (e.g

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“…These patients were mostly elderly and had multiple comorbidities, including advanced renal failure, hepatic failure, heart failure, myocardial infarction and septicaemia [22][23][24]. The mortality of cases of metformin-associated lactic acidosis published before 1996 was 40-50% [23].…”

Section: Metformin and Lactic Acidosis: Association Vs Causalitymentioning

confidence: 99%

“…In 1995, 1 year after metformin had become available in the USA, the retrospectively estimated incidence was 5.0 per 100,000 patient-years, with restrictive prescribing presumably still the norm [22]. The incidence reported for a Canadian region was 9 per 100,000 patient-years [21].…”

Section: Incidence Of Lactic Acidosis In Metformin-treated Patientsmentioning

confidence: 99%

Contraindications can damage your health—is metformin a case in point?

2005

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Metformin is an effective anti-hyperglycaemic and cardioprotective agent, but a long list of contraindications precludes millions of patients with type 2 diabetes from using it. This is largely due to the historical experience of lactic acidosis with phenformin, despite the fact that metformin does not predispose to this when compared with other therapies. Contraindications such as old age, renal impairment and cardiac insufficiency are increasingly disregarded in clinical practice, yet there is no evidence that the incidence of lactic acidosis has changed. Metformin has been shown to improve metabolic control without causing lactic acidosis in elderly patients with multiple comorbidities, including explicit contraindications, and its use in patients with type 2 diabetes over the age of 70 with mild renal impairment did not produce a clinically relevant increase in plasma lactate. There is no correlation between levels of metformin and lactate in patients with lactic acidosis, and its prognosis is mainly related to the causal hypoxic underlying disease and comorbidities. These findings raise doubts about the pathogenetic significance of metformin in lactic acidosis. We propose that advanced age per se, mild renal impairment and compensated heart failure can no longer be upheld as contraindications for metformin. A clear re-definition of contraindications to metformin will enable more physicians to prescribe within guidelines.

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Lactic Acidosis in Patients with Diabetes Treated with Metformin

Cited by 372 publications

References 3 publications

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

Drug-induced acid-base disorders

Contraindications can damage your health—is metformin a case in point?

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