The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a heavier impact on certain subgroups of the population, with notable risk factors being diabetes, obesity, hypertension, cardiovascular disease and advanced age.
A new study by researchers in China and the U.S. describes a round-up of the effects of commonly used hypoglycemic drugs on the outcomes of COVID-19 in diabetic patients.
The research team’s findings have been released on the medRxiv* preprint server.
The role of inflammation
There is a consensus that an exaggerated immune response underlies the progression of COVID-19 to severe and critical stages. This is the result of the uncontrolled release of high levels of inflammatory mediators or cytokines into the tissues, causing inflammatory damage to multiple organs. The presence of what is known as a “cytokine storm” thus correlates with adverse outcomes in COVID-19.
While diabetes has been established to be a risk factor for short-term mortality in hospitalized COVID-19 patients, the role of the drugs used to treat diabetes is less well known. The drugs in common use include metformin, dipeptidyl-peptidase 4 inhibitors (DPP-4i), sulfonylurea, glinides, sodium-glucose co-transporter 2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), α-glycosidase inhibitors and thiazolidinediones (TZDs).
All these are approved and effective drugs, with a good safety profile. They not only reduce the blood glucose levels, but have anti-inflammatory and antiviral effects.
Earlier evidence on hypoglycemic drugs in COVID-19
Metformin is among the most widely used first-line drugs for diabetes. Despite five ongoing clinical trials, this drug is still not seen to have either clearly beneficial or harmful effects on the outcome of COVID-19. DDP-4i may not protect diabetics from being infected with SARS-CoV-2, but could possibly prevent organ failure and fibrosis of the lung secondary to pneumonia in such patients with COVID-19.
Another study showed that SGLT-2i could reduce the SARS-CoV-2 infection rates among diabetic patients.
Despite these preliminary findings, much remains unknown. The current study aims to understand how these drugs affect mortality and the composite outcome of COVID-19 in people with diabetes.
The study shows that metformin-using diabetics with COVID-19 have lower odds of death by 44%. When adjusted for variables like geographical location and time of use, whether in hospital or earlier, the odds were lowered still more, by 60%.
This effect was associated with the prior use of metformin at home, with its use in Europe but not Asia or North America. However, composite outcomes were unaffected.
The reasons for the lack of efficacy of in-hospital metformin use may relate to a higher risk of metabolic acidosis in hospitalized patients, who are likely to already have moderate to severe COVID-19. In such cases, the use of metformin would aggravate the crisis rather than alleviate it.
Indeed, hospitalized diabetics with COVID-19 are put on insulin, switching from metformin, for this reason.
Although the overall benefits of metformin were more evident in Europe relative to the U.S., the researchers found that the home use of metformin by female diabetics with COVID-19 appeared to be linked to reduced mortality, perhaps via an inflammation-modulatory pathway involving TNF-α. The influence of female sex and race need to be excluded, however.
The lack of benefit from metformin use on composite outcomes, such as the requirement for tracheal intubation, acute respiratory distress syndrome (ARDS), admission to the intensive care unit (ICU), and disease progression, may indicate that its main benefit relates to preventing death in severe or critical COVID-19. It may not arrest the disease course itself.
Its mechanisms of action may include inhibition of the IL-6-mediated inflammatory signaling pathway, preventing lung fibrosis and endocytosis, and thus enhancing the expression of angiotensin-converting enzyme 2 (ACE2). The latter is known to improve cardiopulmonary function in COVID-19 patients via its activation of AMP-activated protein kinase (AMPK).
AMPK activation leads to the phosphorylation of ACE2, preventing the virus from binding to this receptor by steric hindrance, and hence reducing the spread of the virus between cells.
Metformin also raises the pH of the cell, thus preventing optimal conditions for endocytosis and viral fusion with the cell membrane, and thus the entry of the virus into the cell. Another possible action is via the reduction of macrophage-derived proinflammatory cytokines and the production of neutrophil extracellular traps (NETs). Further research will allow a better understanding of how metformin operates to reduce the risk of death in diabetics with severe COVID-19.
Available evidence fails to show any reduction of the risk of death or adverse outcomes in people with diabetes with COVID-19 on DPP-4i.
These drugs are hypothesized to have a number of beneficial actions, including inhibition of tissue remodeling by preventing the activation of myofibroblasts and the migration of fibroblasts; suppression of inflammation; and blocking vascular smooth muscle proliferation. These actions could prevent lung fibrosis as well as injury to the heart and kidneys.
As DPP-4 is a putative receptor for the virus, these drugs could also prevent the entry of the virus into cells. Interestingly, however, the serum concentration of soluble DPP-4 is lower in severe COVID-19 patients relative to controls, which throws doubt on the actual protective effects of DPP-4i.
Other hypoglycemic drugs
The study showed that other drugs or drug combinations, such as sulfonylurea and glinides, lacked evidence of any efficacy on outcomes in people with diabetes that had COVID-19.
What are the implications?
The finding of an earlier cohort study that the use of long-term hypoglycemic drugs was associated with reduced COVID-19 mortality in diabetic patients raised hopes that this group of patients would be benefited. The current paper shows that such improvements in mortality are linked only to metformin use, especially when used at home.
While in vitro studies suggest that other hypoglycemic drugs have theoretical (or in vitro) beneficial effects in COVID-19-positive people with diabetes, the paucity of data precludes any substantive conclusions. Metformin also had little impact on composite outcomes.
It should be noted that even for metformin, the data is highly heterogeneous, and the findings should therefore be applied with caution.
More prospective research studies, especially RCTs, are needed to verify and explore the effects of hypoglycemic agents on COVID-19 in diabetic patients,” conclude the researchers.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.