Non-Insulin Novel Antidiabetic Drugs Mechanisms in the Pathogenesis of COVID-19

Abstract

The present study aimed to analyse the published data and to realize an update about the use and pathogenesis of the novel antidiabetic drugs, respectively, dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 Ra), and sodium-glucose co-transporter-2 inhibitors (SGLT-2i), in patients with type 2 diabetes mellitus (T2DM) and coronavirus disease (COVID-19). Literature research in the PubMed and Web of Science database was performed in order to identify relevant published clinical trials and meta-analyses that include information about the treatment with novel antidiabetic agents in patients with T2DM and COVID-19. A total of seven articles were included, and their primary and secondary outcomes were reported and analysed. DPP-4i has mixed results on mortality in T2DM patients with COVID-19 but with an overall slightly favourable or neutral effect, whereas GLP-1 Ra seems to have a rather beneficial impact, while SGLT-2i may be useful in acute illness. Even if there are limited data, they seem to have favourable efficacy and safety profiles. The available evidence is heterogenous and insufficient to evaluate if the benefits of non-insulin novel antidiabetic drugs in COVID-19 treatment are due to the improvement of glycaemic control or to their intrinsic anti-inflammatory effects but highlights their beneficial effects in the pathogenesis and evolution of the disease.

Noninsulin‐based antihyperglycemic medications in patients with diabetes and COVID‐19: A systematic review and meta‐analysis

“…Owing to its interaction with ADA, DPP‐4 facilitates immune cell migration and diapedesis 45 . As a result of reducing cytokine storms, DPP‐4i plays a role in preventing acute respiratory distress syndrome 48,50,51 . In addition, DPP‐4i has also been speculated to have antifibrotic effects because DPP‐4 is known to stimulate the production of cytokines and chemokines by fibroblasts and the proliferation of smooth muscle cells.…”

“… 45 As a result of reducing cytokine storms, DPP‐4i plays a role in preventing acute respiratory distress syndrome. 48 , 50 , 51 In addition, DPP‐4i has also been speculated to have antifibrotic effects because DPP‐4 is known to stimulate the production of cytokines and chemokines by fibroblasts and the proliferation of smooth muscle cells. Therefore, DPP‐4i may prevent lung fibrosis progression and reduce mechanical complications associated with COVID‐19.…”

COVID-19 and metabolic syndrome

“…Benefits and risks of common medications used in metabolic syndrome management in the setting of COVID-19 are an area of intense research and discussion and have been reviewed in detail elsewhere [68] , [69] , [70] , [71*] , [72] , [73] . Data from meta-analyses [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , observational studies [25] and randomized controlled trials [84] , [85*] , [86] , [87] , [88*] , [89] have emerged while several studies are on-going.…”

“… Medication / class Mechanisms a Clinical evidence Implications for practice Impact of long term use on COVID-19 outcomes Impact of use during COVID-19 infection On-going trials Metformin Possible benefit through favourable immunomodulation, inactivation of ACE2 and insulin sensitization [74] ↓ mortality (MOB) b [74] ↑ lactic acidosis ↔ outcomes (RCT) [84] metformin [NCT04625985, NCT04510194] Continue during pandemic / acute infection – guided by standard cautions / contraindications Consider risks of AKI, DKA with SGLT2 inhibitors Lactic acidosis with metformin SGLT2 inhibitors Possible benefit through favourable immunomodulation, decrease RAS activity and vascular oxidative stress [68] ↓ mortality (MOB) b [75] ↔ outcomes No safety concerns (RCT) c [85] empagliflozin [NCT04381936], dapagliflozin [NCT04393246] GLP1 receptor agonists Possible benefit through favourable immunomodulation. Enhancing ACE2 expression – increases risk of viral entry, but decreases in inflammatory response [68] ↓mortality (MOB) b [76] - semaglutide [NCT04615871] DPP4 inhibitors Possible benefit through favourable immunomodulatory and anti-fibrotic effects [68] ↓ or ↔ mortality (MOB) b [78] ↓ mortality (MOB) b [78] linagliptin [NCT04542213], sitagliptin [NCT04365517] Insulin Possible harm through proinflammatory response and formation of reactive oxygen species [69] ↑mortality (MOB) b …”

DPP-4 Inhibitors as a Savior for COVID-19 Patients with Diabetes

“…Cell entry of SARS-CoV-2 is at least partly regulated by the membrane-bound DPP-4 [ 12 ]. These studies, taken together, indicate the potential role of DPP-4 inhibitors in antagonizing the effects of the virus [ 21 , 51 , 52 ]. Continued use of DPP4 inhibitors in hospitalized patients have been found to reduce mortality of COVID-19 patients [ 53 , 54 ].…”