A New Drug–Drug Interaction Between Hydroxychloroquine and Metformin? A Signal Detection Study

Abstract

Introduction Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. Objective The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. Methods Using VigiBase ® , the WHO pharmacovigilance database, we performed a disproportionality analysis (case/noncase study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. Results Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). Conclusion Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.

Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions

“…It was shown that in northern Italy COVID-19 patients experienced significant elevated plasma concentrations of direct oral anti-coagulants while on medications used in the course of COVID-19 [ 10 ]. Unfortunately, with the exception of hydroxychloroquine and QTc-time prolongation due to co-administration of other drugs, the issue of potential harmful DDI in COVID-19 comorbid patients seems to be of minor attention with a limited number of published studies currently available [ [11] , [12] , [13] , [14] , [15] ]. Also, of a public health concern is the use of self-medication being potentially harmful or without evidence of clinical benefit taking place particularly in low- and middle-income countries with restricted access to quality healthcare and where drug dispensing is less controlled in the communities [ 16 , 17 ].…”

Metformin and Covid-19: Focused Review of Mechanisms and Current Literature Suggesting Benefit

“…Additionally, the incidence of heart failure was significantly lower in the metformin group compared to the non-metformin group (adjusted HR, 0.61; 95% CI, 0.43-0.87; p = 0.006) (19). An analysis of individual case safety reports of persons with Covid-19 on hydroxychloroquine suggested an increased risk of mortality associated with hydroxychloroquine + metformin use (ROR value of 57.7 (23.9-139.3) compared to hydroxychloroquine use alone (16). The authors found autophagosomes in mice treated with both, and hypothesized that the excess mortality was from a synergistic inhibition of autophagy (16).…”

“…An analysis of individual case safety reports of persons with Covid-19 on hydroxychloroquine suggested an increased risk of mortality associated with hydroxychloroquine + metformin use (ROR value of 57.7 (23.9-139.3) compared to hydroxychloroquine use alone (16). The authors found autophagosomes in mice treated with both, and hypothesized that the excess mortality was from a synergistic inhibition of autophagy (16). Caution should be considered for co-administration in humans.…”

The Current and Potential Therapeutic Use of Metformin—The Good Old Drug

“…Long-term clinical experience supported by numerous clinical studies clearly indicates that a substantial percentage of T2DM patients do not achieve the expected level of glycemic control while receiving metformin in monotherapy [ 278 ]. Considerable intra-individual variability in metformin response may be caused by numerous factors such as: age, gender, physical inactivity, insufficient dose of the drug, non-adherence, interaction between metformin and other drugs and metformin interaction with microbiota [ 279 , 280 ]. Experimental and clinical studies in both healthy volunteers and diabetic patients have shown that specific groups of genes (e.g., the family of SLC genes) are involved in metformin absorption, distribution, metabolism and elimination and, as a result, may affect the pharmacological response to this drug [ 281 , 282 , 283 , 284 , 285 ].…”