Metformin-Associated Lactic Acidosis

Pasquel, Francisco J.; Hinedi, Ziad; Umpiérrez, Guillermo E.; Klein, Robin; Adigweme, Adaeze; Coralli, Richard J.; Pimentel, Juan; Lopez, Fred A.

doi:10.1097/maj.0b013e3182a562b7

Cited by 42 publications

(25 citation statements)

References 53 publications

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“…Metformin is a first-line drug for type 2 diabetic patients and the main mechanism of metformin's anti-diabetic action is believed to be inhibition of complex I in the electron transport chain, which in turn inhibits hepatic gluconeogenesis [68]. This is linked to a risk of lactic acidosis [95] and therefore, metformin administration can be dangerous in some patients and is usually not recommended for diabetic patients with heart failure [96]. A more recent opinion, however, considers the risk of metformin in diabetic patients with heart failure as minimal and suggests that the cardioprotective benefit outweighs this risk [97].…”

Section: Metforminmentioning

confidence: 99%

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Timm

Tyler

2020

Cardiovasc Drugs Ther

121

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Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate-activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.

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Section: Metforminmentioning

confidence: 99%

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Timm

Tyler

2020

Cardiovasc Drugs Ther

121

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“…Lactic acidosis is defined as a pH < 7.35 and a lactate concentration greater than 5 mmol/L . Anaerobic glycolysis generates pyruvate which is then reduced in the cytosol of highly glycolytic tissues to lactate via lactate dehydrogenase .…”

Section: Discussionmentioning

confidence: 99%

“…There was no clear relationship between the dose of metformin and the development of lactic acidosis . Since 1988, the reported incidence of MALA is variable throughout the literature ranging from zero to 138 cases per 100,000 patient‐years . In 2010, a Cochrane meta‐analysis of 347 prospective and observational cohort studies did not identify any cases of lactic acidosis in 70,490 patient‐years of metformin exposure .…”

Section: Discussionmentioning

confidence: 99%

Hypoglycemia and severe lactic acidosis in a dog following metformin exposure

Barrella¹,

Eisenberg²,

Simpson³

2017

Clinical Case Reports

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“…phenformin and buformin. Metformin might induce lactic acidosis in patients with renal insufficiency, therefore it is not prescribed in this subgroup of patients with T2D (11). Metformin is in clinical use since 1959 but its molecular mechanisms of action are still not entirely understood.…”

Section: Biguanides (Metformin)mentioning

confidence: 99%

Pharmacogenetics of Oral Antidiabetic Therapy

et al. 2018

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Type 2 diabetes prevalence is still on the rise worldwide. Antidiabetic drugs are widely prescribed to patients with Type 2 diabetes. Most patients start with metformin which is mostly well tolerated. However, a high percentage of patients fail to achieve glycemic control. The effectiveness of metformin as well as most other antidiabetic drugs depends among other factors on interindividual genetic differences that are up to now ignored in the treatment of Type 2 diabetes. Interestingly, many genes influencing the effectiveness of antidiabetic drugs are Type 2 diabetes risk genes making matters worse. Here, we shed light on these interindividual genetic differences.

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Metformin-Associated Lactic Acidosis

Cited by 42 publications

References 53 publications

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Hypoglycemia and severe lactic acidosis in a dog following metformin exposure

Pharmacogenetics of Oral Antidiabetic Therapy

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