Antihyperglycemic properties of hydroxychloroquine in patients with diabetes: Risks and benefits at the time of COVID‐19 pandemic

Abstract

The antimalarial drug hydroxychloroquine (HCQ) has long been used as a disease-modifying antirheumatic drug for the treatment of several inflammatory rheumatic diseases. Over the last three decades, various studies have shown that HCQ plays also a role in the regulation of glucose homeostasis. Although the mechanisms of action underlying the glucose-lowering properties of HCQ are still not entirely clear, evidence suggests that this drug may exert multifaceted effects on glucose regulation, including improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance and reduction of systemic inflammation. Preliminary studies have shown the safety and efficacy of HCQ (at a dose ranging from 400 to 600 mg/day) in patients with type 2 diabetes over a short-term period. In 2014, HCQ has been approved in India as an addon hypoglycemic agent for patients with uncontrolled type 2 diabetes. However, large randomized controlled trials are needed to establish the safety and efficacy profile of HCQ in patients with type 2 diabetes over a long-term period. With regard to the COVID-19 pandemic, several medications (including HCQ) have been used as off-label drugs due to the lack of proven effective therapies.However, emerging evidence shows limited benefit from HCQ use in COVID-19 in general. The aim of this manuscript is to comprehensively summarize the current knowledge on the antihyperglycemic properties of HCQ and to critically evaluate the potential risks and benefits related to HCQ use in patients with diabetes, even in light of the current pandemic scenario. Highlights Hydroxychloroquine (HCQ) has been shown to exert antihyperglycemic properties by virtue of potential multifaceted effects on glucose homeostasis, including improvement of insulin sensitivity, increase of insulin secretion and reduction of systemic inflammation. This article is protected by copyright. All rights reserved. Accepted Article Preliminary studies have shown the safety and efficacy of HCQ as an antihyperglycemic agent in type 2 diabetes over a short-term period. A careful risk-benefit assessment of HCQ is critical for a cautious use of this drug in diabetic patients, particularly in light of the current COVID-19 pandemic.

Efficacy and safety of hydroxychloroquine as add-on therapy in uncontrolled type 2 diabetes patients who were using two oral antidiabetic drugs

“…Antihypoglycemic property of hydroxychloroquine in patients with diabetes and the risk benefits at the time of COVID-19 pandemic is major subject of discussion. Emerging evidence with regards to the current pandemic scenario shows that following COVID-19 infection diabetic patients have a greater risk for adverse outcomes [52]. There are several review articles published which support the effect of hydroxychloroquine in the early infection stage of COVID-19 [53][54][55].…”

What Every Diabetologist Should Know about SARS-CoV-2: State of Knowledge at the Beginning of 2021

“…It has been shown that hydroxychloroquine (HCQ) can be successfully used in patients with diabetes due to its hypoglycemic effect [ 72 , 91 ]. The mechanisms by which the drug affects glycemic control are still not entirely clear, however, it is suggested that it improves insulin sensitivity, increases insulin secretion, reduces hepatic insulin clearance, and reduces systemic inflammation [ 92 ]. This drug appeared to be effective in treating COVID-19 [ 72 , 91 ].…”

Hydroxychloroquine in the COVID-19 pandemic era: in pursuit of a rational use for prophylaxis of SARS-CoV-2 infection

“…Moreover, HCQ may influence the activity of the High mobility group box 1 protein (HMGB1) [ 38 ], which is a ubiquitous and highly conserved endogenous damage-associated molecular pattern (DAMP) molecule involved in the pathogenesis of several inflammatory conditions [ 39 , 40 ]. In light of these mechanisms of action, HCQ may theoretically exert an indirect antiviral activity by reducing the low-grade systemic inflammation, which is a common feature of several chronic diseases (e.g., obesity, type 2 diabetes, and metabolic syndrome) that are associated with an increased prevalence of SARS-CoV-2 infection and adversely affect the outcomes of patients with COVID-19 [ 41 , 42 ]. Intriguingly, relatively low rates of hospital PCR-confirmed COVID-19 cases have been reported in patients with SLE and inflammatory arthritis when compared to patients with systemic autoimmune or immune-mediated rheumatic diseases, despite an expected greater use of immunosuppressants and corticosteroids [ 43 ].…”

“…Some of the most serious HCQ-related side effects include retinal toxicity [ 12 , 79 ], neuromyotoxicity [ 80 – 85 ] and cardiotoxic effects leading to potentially lethal heart rhythm disorders, such as prolonged QT interval and ventricular arrhythmias [ 12 , 86 – 88 ]. Besides excluding subjects with known hypersensitivity to HCQ or 4-aminoquinoline compounds, upcoming trials investigating the use of HCQ should also consider to exclude the enrollment of patients with underlying coexisting conditions that increase the risk of HCQ-related side effects, such as: i) patients with preexisting retinopathy/maculopathy or history or risk for macular edema [ 89 , 90 ]; ii) patients with preexisting cardiomyopathy, heart failure, ventricular hypertrophy, left ventricular dysfunction, coronary artery disease and/or heart rhythm disorders such as long QT syndrome [ 27 , 91 – 93 ]; iii) diabetic patients with macrovascular and/or microvascular complications [ 42 ]; iv) electrolyte abnormalities such as hypokalemia and hypomagnesemia [ 93 ]; v) family history of premature sudden cardiac death or cardiac ion channelopathies [ 91 – 93 ]; vi) patients with preexisting myopathy and/or neuropathy; vii) patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency [ 94 , 95 ], although chloroquine- and HCQ-induced hemolysis in subjects with G6PD-deficiency has not been conclusively proven [ 96 ]; viii) patients using certain concomitant QT interval-prolonging medications such as azithromycin [ 22 , 91 – 93 ]. Thus, baseline and follow-up electrocardiography to evaluate for prolonged QT interval may be advisable prior to and following the initiation of HCQ, even in clinical trial settings.…”