Comment on “Is the type of diabetes treatment relevant to outcome of COVID‐19?”

Dear Editor:

We read with interest the editorial entitled “Is the type of diabetes treatment relevant to outcome of COVID‐19?” ¹ The concept of harnessing the pleiotropic anti‐inflammatory properties of antidiabetic medications in the management of early/advanced coronavirus disease 2019 (COVID‐19) in people with diabetes mellitus (DM) is intriguing. However, translation into clinical practice requires more justifications.

Thiazolidinediones reduce cardiovascular events in terms of recurrent myocardial infarction/stroke in people with type 2 DM (T2DM). ² , ³ However, pioglitazone use is also associated with an increased risk of heart failure (HF) in patients with and without pre‐existing cardiovascular disease. ⁴ , ⁵ , ⁶ Increased plasma volume secondary to fluid retention is attributed as the cause of HF. ⁷ A significant number of COVID‐19 patients develop cardiac complications with the cause of death attributed to cardiac failure/arrest in 25% of cases. ⁸ , ⁹ Isolated cardiac involvement has also been reported. ¹⁰ It is believed that COVID‐19 induces a state of classic HF with preserved ejection fraction in early stages that later culminates into acute systolic HF amid a state of cytokine storm, biochemically manifesting as elevated troponin and natriuretic peptides. ⁹ HF is likely to be exacerbated with use of pioglitazone; in fact, the drug has been associated with significant elevation in natriuretic peptides. ¹¹ Moreover, pioglitazone has been shown to upregulate angiotensin‐converting enzyme 2 (ACE2). ¹² , ¹³ , ¹⁴ Upregulation of ACE2 may be counterproductive as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) uses ACE2 as a receptor for entry into host cells. Although pioglitazone does have anti‐inflammatory properties independent of its glucose‐lowering effect, it is debatable whether it would be of any benefit in COVID‐19. Even corticosteroids, potent anti‐inflammatory drugs, have not been found to be beneficial in COVID‐19. ¹⁵

Hydroxychloroquine/chloroquine is being used against COVID‐19 although available studies have not shown any mortality benefit. ¹⁶ , ¹⁷ In addition, many patients developed QT prolongation. ¹⁸ , ¹⁹ , ²⁰ It is not universally accepted as an antidiabetic agent either and is not Food and Drug Administration (FDA) approved for this purpose. Moreover, robust double‐blinded, randomized controlled trials demonstrating its glucose‐lowering efficacy are very limited, ²¹ , ²² most being either open‐label/real‐world/observational studies. Besides, it has primarily been evaluated as a third‐line antidiabetic drug in patients with poor glycemic control; in the present scenario, insulin would be a better choice in such patients. ¹⁴ Thus, in absence of robust clinical data favoring its use in either COVID‐19 or T2DM, advocating hydroxychloroquine for its anti‐inflammatory effects is certainly not wise.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) are also known for their anti‐inflammatory properties, both at systemic and tissue level. ²³ , ²⁴ , ²⁵ However, it is always advisable to withhold SGLT2i in the presence of any active infection as it increases the chances of euglycemic diabetic ketoacidosis. Moreover, patients on SGLT2i are at a higher risk of dehydration and acute kidney injury amid the already increased insensible water loss precipitated by fever and tachypnea. ²⁶ , ²⁷

Thus, while choosing an antidiabetic drug in patients with COVID‐19, a physician should take into account the therapeutic efficacy and potential adverse effects of the drug, rather than its anti‐inflammatory properties. Most often, insulin happens to be the best option in hospitalized patients with COVID‐19 and DM.

CONFLICT OF INTEREST

None.