|Year : 2020 | Volume
| Issue : 4 | Page : 191-193
Managing type 2 diabetes during COVID-19: Unanswered questions and key issues
Department of Medicine, Kasturba Hospital, Manipal, Karnataka, India
|Date of Submission||18-Aug-2020|
|Date of Acceptance||01-Sep-2020|
|Date of Web Publication||5-Jan-2021|
Professor, Department of Medicine, Kasturba Hospital, Manipal 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Vidyasagar S. Managing type 2 diabetes during COVID-19: Unanswered questions and key issues. J Clin Sci Res 2020;9:191-3
The high prevalence of diabetes in India makes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease (COVID-19) pandemic a serious problem for this vulnerable population. There are several unanswered questions and key issues to be addressed in this combination of diseases, including the impact of diabetes on COVID-19 risk, the severity of disease in this subgroup and the management of both diseases in combination.
Diabetics, in general, are prone to infections, however the risk for COVID-19 is not higher in diabetics. Theoretically, diabetics have increased levels of furin, which is Type-1 membrane-bound protease, known to increase viral replication and allow entry of coronaviruses into the cell. Furthermore, the expression of angiotensin-converting enzyme 2 (ACE2) receptor which is the point of viral entry into the cell is also increased in diabetic patients. However, several meta-analyses have shown clearly that this does not translate into clinically increased prevalence. Data from several countries such as China and the European Union showed that the prevalence of diabetes in COVID patients was the same as the general population in those countries.
However, when we look at the cohort of severe COVID infections, diabetics form one-third of this group. They also tend to have more severe lung involvement, higher neutrophil–lymphocyte ratio and lactate dehydrogenase, with lower oxygenation and more prolonged hospital course. The reason for this could be that diabetes is a pro-inflammatory state with an exaggerated cytokine response causing a vigorous cytokine storm.
Furthermore, the mortality among diabetics who had severe COVID is much higher than the general population. In a meta-analysis. of 33 studies it was found that diabetics have a two-fold increase in mortality, compared to non-diabetic patients and in addition had a higher rate of intensive care unit (ICU) admission and ventilatory requirement. Further, diabetics are likely to be older, have hypertension or ischemic heart disease or chronic kidney disease, all of which add to the morbidity and mortality of COVID patients.
ACE2, in normal life, has a regulatory function on the renin–angiotensin–aldosterone system. It cleaves angiotensin I (Ang I), generating Ang 1–9 and Ang II to produce Ang 1–7. These have vasodilator, anti-proliferative and anti-fibrotic effects which are diametrically opposed to Ang II and hence, ACE2 is protective.
The COVID-19 virus uses the ACE receptor as an entry point to invade the cell. Chronic hyperglycaemia downregulates these receptors and may actually protect from viral entry theoretically. However, this negates the role of ACE2 in producing vasodilatory and anti-proliferative substances. Hence, diabetics are prone to more severe disease in the lung causing ARDS and fibrosis.
Hyperglycaemia is well known to worsen course and prognosis of all major illnesses in the ICU. In COVID-19 too, patients with higher blood sugars had worse outcomes. In fact, mortality was higher in patients with hyperglycaemia, by four times (28.8% vs. 6.2%) in a New York series. Further, the incidence of diabetic ketoacidosis and hyperosmolar syndrome is also higher. In the CORONADO study, 11.1% of the participants had diabetes-related disorders at admission including 132 patients with severe hyperglycaemia and 40 with ketosis, of whom 19 had diabetic ketoacidosis.
The reason for this could be that apart from the general tendency of all infections to worsen hyperglycaemia, this virus binds to ACE2 receptor sites on the pancreatic beta cells causing severe insulin deficiency which may precipitate ketosis. Further, the dehydration associated with hyperosmolar syndrome may also increase the prothrombotic tendency of COVID-19 and lead to a worse prognosis.
There is another subgroup of stress hyperglycaemia in these patients, who typically have a higher mortality than known diabetics. Further, there is a new-onset diabetes group, during COVID-19 illness, in whom too, mortality is more than those with even established diabetes.
For stable patients of diabetes, the COVID pandemic may have pushed some of them into hyperglycaemia, due to lack of exercise due to lockdown, mental stress, lack of access to healthy food, medical help and medications. Teleconsultation has picked up during this period and made some difference in the care of this vulnerable subgroup.
It is well known that control of blood sugars is crucial for the better prognosis in patients with COVID-19, and this brings up the question of the ideal therapy in this setting. For patients with severe COVID-19 in the ICU, insulin infusion should be the choice with the usual recommendations of keeping blood sugars in a narrow range of 140 mg/dl to 180 mg/dl. Metformin runs the risk of lactic acidosis in the presence of renal dysfunction or shock, and sodium-glucose cotransporter 2 inhibitors can cause dehydration and euglycemic ketoacidosis in this patient group with a delicately balanced volume status. Pioglitazone has been mooted to decrease the cytokine storm by decreasing the secretion of pro-inflammatory cytokines, but this has not been substantiated clinically. Glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors are reasonably safe but have drug interactions with many protease inhibitors which may be used for the treatment of COVID-19.
Several drugs used to treat COVID-19 can impact diabetes. Hydroxychloroquine can cause hypoglycaemia, whereas lopinavir ritonavir can cause hyperglycaemia. Steroids are used in patients with hypoxia, following their beneficial effects as shown in the RECOVERY trial. However, they can cause severe hyperglycaemia, which should be kept in mind and treated appropriately. It has also been mooted that diabetics with COVID could shed the virus for longer periods than others and steroid use in them could increase this duration.
Many patients with diabetes mellitus could be on these drugs for hypertension and proteinuria. The COVID pandemic has brought into focus the role of ACE inhibitors and angiotensin receptor blockers which may increase the expression of ACE2 by 2–5 fold. This may theoretically increase the risk of contracting COVID-19, but protect them from severe disease. However, there is no hard evidence to prove that they are harmful or useful, hence major cardiology and hypertension societies recommend their continuation in all patients. In fact, there are studies to show that these drugs may actually be protective and improve prognosis in COVID patients.
The absence of very effective antiviral drugs or a vaccine has sparked speculation about trying to tackle COVID-19 in novel ways. It has been found that SARS-CoV-2 has a receptor-binding domain that harbours a single mutation which greatly increases its binding affinity to ACE2. Thus, blocking the ACE2 receptor binding site either by monoclonal antibodies or developing an ACE2 like protein which could bind and neutralise the SARS-CoV-2, before it attacks the cell has all been theorised., However, these options are not easy and will have to take into account the number of ACE2 receptors in the lung, where this receptor may actually have a protective effect, and hence, this strategy may backfire.
The mortality of COVID being higher in certain populations has also been researched. It has been proposed that the genetic variations may account for ethnic variability seen in the American population. Polymorphisms of the ACE gene may account for differing prognosis in various ethnic groups too. This too may be an area of research to bring down mortality.
To conclude, it is important that diabetic patients must be protected from COVID-19, as they tend to have more severe disease and more mortality. During their hospital course too, their sugars must be well controlled, keeping in mind drug interactions. Managing both diabetes and COVID is a challenge but can be met with effectively, with the awareness of the seriousness of this combination and careful strategy to bring down mortality.
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