Use of pioglitazone in people with type 2 diabetes mellitus with coronavirus disease 2019 (COVID-19): Boon or bane?

Abstract

Background and aims People with type 2 diabetes mellitus (T2DM) have increased morbidity and mortality due to coronavirus disease-19(COVID-19). It has been speculated that use of pioglitazone might increase such risk. The aim of our brief commentary is to review the safety of pioglitazone in people with T2DM and mild/moderate COVID-19. Methods We searched PubMed database using specific keywords related to our aims till May 15, 2020. Full text of relevant articles published in English language were retrieved and reviewed. Results Medications, including pioglitazone, that upregulate tissue expression of angiotensin converting enzyme 2 (ACE2), might have a dual role in COVID-19; on the one hand they might increase risk of infection as SARS-CoV2 uses ACE2 as a coreceptor to enter alveolar cells, but on the other hand, by reducing angiotensin II levels, they can protect against acute lung injury. There is no evidence to date that pioglitazone upregulates ACE2 in the alveolar cells; rather, there is evidence from animal studies of upregulation of ACE2 in insulin sensitive tissues, which might have a protective effect on lung injury. Moreover by moderating the exaggerated host proinflammatory response, pioglitazone can potentially reduce SARS-CoV-2 driven hyperinflammation. Conclusions Pioglitazone has more potential for benefit than harm, and can be continued in people with T2DM and mild/moderate COVID-19, unless there are specific contraindications for its use. There is an urgent need to assess clinically relevant outcomes in people with diabetes and COVID-19 based upon baseline antidiabetes therapy, in particular pioglitazone.

COVID-19 in Relation to Hyperglycemia and Diabetes Mellitus

“…For this reason, SARS-CoV-2 pathophysiology is related to its interaction with adipocytes and adipose-like cells that favor the differentiation of lung lipofibroblasts into myofibroblasts ( 79 ). Pioglitazone also increases ACE2 expression in insulin-sensitive tissues, normalizing blood glucose and attenuating acute kidney injury through the amelioration of the expression of renal ADAM17 ( 80 ). Therefore, thiazolidinediones can reduce the interaction between SARS-CoV-2 and adipocytes with subsequent reduction of COVID-19 severity ( Figure 6 ).…”

Interplay of Opposing Effects of the WNT/β-Catenin Pathway and PPARγ and Implications for SARS-CoV2 Treatment

“…Several reports have indicated that PPARg agonists could be candidates for modulating the cytokine storm in the COVID-19 disease (87,149,150). A possible therapeutic role for pioglitazone has been identified with respect to the SARS-CoV-2 infection (16).…”

“…Several studies have shown that, in numerous diseases (11)(12)(13)(14), the WNT/b-catenin pathway interacts with PPARg (peroxisome proliferator-activated receptor gamma) in an opposing interplay, with the effects of one opposing those of the other. Recent studies have also highlighted the possible role of PPARg agonists as modulators of inflammatory and immunomodulatory drugs by targeting the cytokine storm in COVID-19 patients (15,16). This review focuses on the opposing interplay between WNT/b-catenin and PPARg in SARS-CoV-2 infection and the potential role of PPARg agonists in this context.…”

Perspectives of Antidiabetic Drugs in Diabetes With Coronavirus Infections

“…Furthermore, due to its adverse effects such as fluid retention (Alam et al, 2019), pioglitazone was recommended for discontinuation in acutely ill patients. In contrast, Mukherjee et al considered that pioglitazone had more potential benefit than harm, and it could be continued in people with moderate COVID-19 (Jagat et al, 2020). Indeed, pioglitazone has been shown to decrease the secretion of various proinflammatory cytokines in the monocytes and macrophages (Bassaganya-Riera et al, 2010).…”