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Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice

Authors: Rajeshkumar et al. Link to paper: https://doi.org/10.1101/2020.03.31.018556

Journal/ Pre-Print: BioRxiv

Key Words: Chloroquine (CQ), Hydroxychloroquine (HCQ), Metformin, Treatment.

Research Highlights 

1. In mice (nude or C57BL/6) the combination of metformin, one of the most common diabetes drugs, with hydroxychloroquine (HCQ) was fatal in more than 30% of the animals. This effect will have a significant impact on diabetes patients that have COVID-19.

2. LDH levels, which are considered predictive for COVID-19 severity, was increased in mice treated with metformin alone, hydroxychloroquine alone or with a combination of both.

Summary 

Main findings of the study

· Does the paper increase our understanding of COVID19?

· How does the study add to current knowledge?

This study is a cautionary tale for the administration of hydroxychloroquine in COVID-19 metformin-treated patients with diabetes. The authors found that nude or B6 mice treated with metformin and hydroxychloroquine had a 30-40% reduction in survival rate compared to controls. Importantly, the authors found amplified LDH levels in mice treated with metformin, hydroxychloroquine or both. Given that LDH has predictive value for COVID-19 severity, the administration of hydroxychloroquine to diabetic COVID-19 patients may require re-consideration. Since chloroquine and hydroxychloroquine treatment during the COVID-19 pandemic is already widespread, such studies provide us with information as to which patients should be treated with these drugs.

Impact for SARS-CoV2/COVID19 research efforts

Treatment of SARS-CoV2/COVID19 positive individuals: The authors provide a warning for the co-administration of metformin and hydroxychloroquine, which is relevant for diabetes patients who have COVID-19. This study raises new questions about the safety of hydroxychloroquine in the treatment of Covid-19 patients, where the majority of patients are elderly and taking several other drugs for different diseases.

Study Type

· In vivo study (mouse)

Strengths and limitations of the paper

Novelty: The new insight is the caution in using metformin along with hydroxychloroquine in light of the extensive use of chloroquine and hydroxychloroquine during the COVID-19 pandemic.

Standing in the field: While tThere are studies showing that HCQ can be toxic, and there are many studies showing that the HCQ administration is safe and can be used for Covid-19 treatment. This is the first study to demonstrate adverse drug reactions with the use of CQ or HCQ in combination with metformin. Given high LDL levels in severe COVID-19 patients and increased risk for severe disease in diabetic patients, this paper provides important insights into potentially detrimental pharmacological interactions during the SARS-CoV2 pandemic.

Appropriate statistics: Yes

Viral model used: N/A

Translatability: The findings are translatable, greater consideration should be given when prescribing hydroxychloroquine to diabetic patients that might be on metformin treatment.

Main limitations:

· The drug toxicity in mice might be different from the drug toxicity in humans.

· There is a lack of Kaplan-Meier controls of metformin or hydroxychloroquine treatment alone.

· While the authors do not quantify the autophagosome accumulation they observe, they imply that it is higher in the co-treated animals.