key: cord-337898-ncrbd8rp authors: Pal, Rimesh; Banerjee, Mainak title: Comment on “Is the type of diabetes treatment relevant to outcome of COVID‐19?” date: 2020-05-27 journal: J Diabetes DOI: 10.1111/1753-0407.13069 sha: doc_id: 337898 cord_uid: ncrbd8rp nan 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 antiinflammatory properties of anti-diabetic medications in management of early/advanced 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 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 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; infact, it has been associated with significant elevation in natriuretic peptides 11 . Moreover, pioglitazone has been shown to upregulate angiotensin-converting enzyme 2 (ACE2) 12-14 . This article is protected by copyright. All rights reserved. Upregulation of ACE2 may be counterproductive as 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 anti-diabetic agent either and is not FDA approved for this purpose. Moreover, robust doubleblinded, 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 anti-diabetic drug in patients with poor glycemic control; in 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. SGLT2 inhibitors 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 . This article is protected by copyright. All rights reserved. Thus, while choosing an anti-diabetic 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. Funding: None Is the type of diabetes treatment relevant to outcome of COVID -19? The Effect of Pioglitazone on Recurrent Myocardial Infarction Patients With Type 2 Diabetes and Previous Myocardial Infarction Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke: Results From PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04) Pioglitazone Use and Heart Failure in Patients With Type 2 Diabetes and Preexisting Cardiovascular Disease: Data This article is protected by copyright. All rights reserved. from the PROactive Study (PROactive 08) Pioglitazone-induced heart failure despite normal left ventricular function Pioglitazone-induced congestive heart failure and pulmonary edema in a patient with preserved ejection fraction Thiazolidinediones and Heart Failure: A teleoanalysis Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet COVID-19 Illness and Heart Failure Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19) This article is protected by copyright. All rights reserved Effect of pioglitazone on heart function and N-terminal pro-brain natriuretic peptide levels of patients with type 2 diabetes Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3-TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study Should anti-diabetic medications be reconsidered amid COVID-19 pandemic? Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19) Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State This article is protected by copyright. All rights reserved Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19) Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas-a randomized trial Effects of SGLT2 inhibitors on systemic and tissue lowgrade inflammation: The potential contribution to diabetes complications and cardiovascular disease The SGLT2 Inhibitor Empagliflozin Ameliorates the Inflammatory Profile in Type 2 Diabetic Patients and Promotes an Antioxidant Response in Leukocytes Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease This article is protected by copyright. All rights reserved Practical recommendations for the management of diabetes in patients with COVID-19 Reply to comment on "Should anti-diabetic medications be reconsidered amid COVID-19 pandemic? This article is protected by copyright. All rights reserved