Hydroxychloroquine, COVID-19 and diabetes. Why it is a diffe
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In the context of the current COVID-19 pandemic, solutions are being sought worldwide in order to identify the most appropriate treatment for the patients with SARS-COV-2. Hydroxychloroquine (HCQ) or chloroquine have been widely used for the treatment of COVID-19. The use of this class of drugs for COVID-19 was based on a small number of anecdotal experiences that have shown variable responses in uncontrolled observational analyses. HCQ is a well-known antimalarial drug, also used as anti-rheumatic therapy in the systemic lupus erythematosus, rheumatoid arthritis, etc. Chloroquine (CQ) was the first drug that was used as prophylaxis as well as treatment in malaria. HCQ is the most soluble and least toxic metabolite of CQ.

There are two possible mechanisms of action through which CQ/HCQ might combat the SARS-CoV-19 infection: the effect on angiotensin-converting-enzyme-2 (ACE2) receptor and the anti-inflammatory activity. The penetration of the SARS-CoV-19 inside the host cells is achieved through the super expression of the ACE2 on the cell surface, in the lung, heart, kidneys and several other tissues. The virus links to this enzyme and in this way its penetration into the host cell is facilitated. CQ/HCQ blocks the glycosylation of ACE2 by modifying the lysosomal PH, thus preventing the intracellular penetration of the virus, and the effect on sialic acid binding linked to the ganglioside domain on the cell surface. Via MAP-kinase pathway, HCQ interferes with SARS-CoV-2 at an intimate molecular level, modifying the architecture of the virion and facilitating the process of proteolysis of the M protein.

The second kind of action is the anti-inflammatory effect. This effect plays a major role in blocking the inflammatory cytokine production, especially IL-6, thus significantly diminishing the “cytokine storm,” which is responsible for elevated morbidity, as well as mortality, due to the development of multiorgan dysfunction including the “Acute Respiratory Distress Syndrome” (ARDS).

Based on this data, it has been hypothesized that HCQ could be used as a therapy for the SARS-CoV-19 infection. Preliminary data were contradictory and more recent evidence is even more controversial. However, it is worth to mention that the question might be still open. The typical clinical course of COVID-19 infection suggests that the virus load in the respiratory tract increases stepwise starting with mild symptoms and ending in up to 15% of patients with severe and potentially life-threatening pneumonia. Therefore, the treatment with a drug that inactivates the cell receptor for the virus should start after exposition with high risk, for example, when one person has been infected very recently with the virus or is in the early phase of the disease. This hypothesis is new because the major assumption in ongoing clinical studies and actual recommendations is that HCQ and CQ should be used in patients with severe COVID-19 pneumonia and only when other treatment strategies have failed.

Smith et al in 1987 were the first describing a significant improvement of glycaemic values in few people with type 2 diabetes mellitus treated with HCQ. Quatraro et al then sustained this observation in 1990, with a study in type 2 diabetes treated with insulin or glibenclamide associated with HCQ for 6 months. HCQ treatment produced a significant decrease of HbA1C by 3.3% and a reduction of the insulin dose by 30%, among the group treated with insulin, compared to placebo. A recent systematic review evaluating the effect of HCQ in diabetes, including 55 776 study participants, has shown a significant improvement of lipid profile and insulin levels and substantial diminution of haemoglobin A1c, fasting plasma glucose and postprandial blood glucose levels.

The mechanisms through which HCQ produces its anti-hyperglycaemic effects seems to be the increase in insulin action and the alterations in insulin metabolism and signalling through cellular receptors. Anyhow, the management of the anti-diabetic therapy when HCQ is used should be reassessed, because its hypoglycaemic effect may precipitate severe episodes of hypoglycaemia. This possibility was firstly mentioned by Smith et al in 1987.

Unfortunately, it not surprising that during the COVID?19 pandemic emerged that people with diabetes have a worse prognosis, particularly those with uncontrolled glycaemia. It is emerging that the presence of hyperglycaemia worsens the prognosis of people infected with COVID-19. On this basis, it is clear that an optimal glycaemic control is mandatory in people with diabetes to reduce their risk of a complicated COVID-19. Considering the studies described above, it should make sense to implement the first-line treatment in people with diabetes with HCQ. This, however, will require a strict monitoring of other concomitant anti-hyperglycaemic treatments, in order to avoid severe hypoglycaemia.

Source: https://onlinelibrary.wiley.com/doi/full/10.1002/dmrr.3379?af=R