key: cord-0079080-lgy15v7k authors: Koufakis, Theocharis; Popovic, Djordje S.; Metallidis, Symeon; Kotsa, Kalliopi title: COVID-19 and sulfonylureas: A reminder of the pleiotropic actions of an old class of drugs just before their swansong date: 2022-05-26 journal: Metabolism DOI: 10.1016/j.metabol.2022.155221 sha: 66d8a5178b1921b2f206e8fb57de579902cf0f58 doc_id: 79080 cord_uid: lgy15v7k nan To the editor, Sulfonylureas (SUs) have been used for the treatment of hyperglycemia for more than 60 years and are currently the second most commonly prescribed antidiabetic agents worldwide after metformin [1] . Their low cost, the strong glucose-lowering action, and the vast clinical experience with their use have always been attractive features for physicians, health care systems, and scientific societies when discussing the therapeutic strategy for type 2 diabetes (T2D). On the other hand, important concerns over their use, related to the risk of hypoglycemia and weight gain, but primarily to their cardiovascular (CV) safety, never allowed SUs to be considered ideal glucoselowering drugs [2] . Although some recent large trials have been reassuring, showing a neutral effect of the newer SUs on CV outcomes [3] , hypoglycemia per se is known to have a deleterious impact on CV health [4]. During the last few years, humanity has lived in the shadow of the COVID-19 pandemic. Suboptimal glycemic control has been associated with an increased risk of mortality and poor outcomes in infected patients [5] . Surprisingly, despite the established association between COVID-19 and CV complications [6] , a recently published, large meta-analysis including data from 3,061,584 individuals [7] demonstrated a neutral effect of therapy with SUs prior to infection on COVID-19related mortality. The findings were adjusted for several confounders such as age, race, body weight, presence of hypertension, and chronic kidney disease. Two previous meta-analyses had shown that SUs could be associated with a reduced mortality risk in patients with T2D who have COVID-19 [8, 9] . The results should be Tumor Necrosis Factor, Interleukin (Il)-6, and C-Reactive Protein (CRP) [10] . In a study comparing metformin monotherapy with glyburide, only the latter was able to promote a significant decrease in CRP levels within a short period of time (3 months) [11] . Cytokine storm release is known to be associated with rapid clinical deterioration in patients with COVID-19 [12] . Glyburide has been shown to downregulate the expression of the pro-inflammatory cytokines IL-1β and IL-18 and reduce mRNA expression in macrophages isolated from wounds [13] . In addition, it has been demonstrated to inhibit the NLRP-3 inflammasome in a model of diabetesinduced fracture healing [14] . Taken together, these indicative data imply that the adverse relationship observed between SU treatment and mortality in people with COVID-19 could be mediated by the anti-inflammatory properties of this drug category. The cost of antidiabetic treatment remains an issue in many places around the world. However, considering that the growing burden of diabetes on societies is mainly driven by its complications [15] , it becomes increasingly evident that sooner or later we will have to bid adieu to SUs. The spotlights of medical research are reasonably on the pleiotropic properties of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists and soon on more treatments to come, such as the dual GLP-1 / glucose-dependent insulinotropic polypeptide receptor agonists. In the era of spectacular benefits of the new glucose-lowering agents in terms of alleviating cardiorenal risk, there is no space for debates on the CV safety of antidiabetic drugs. However, the COVID-19 pandemic reminded us of the J o u r n a l P r e -p r o o f Journal Pre-proof largely unexplored pleiotropic actions of an old therapeutic class that probably deserved a closer look. Prescribing pattern and efficacy of anti-diabetic drugs in maintaining optimal glycemic levels in diabetic patients A lion in the room: Has the CAROLINA trial definitely resolved the issue of the cardiovascular safety of sulfonylureas? Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial Diabetes, glycaemic control, and risk of COVID-19 hospitalisation: Population-based Cardiovascular risk and complications associated with COVID-19 Preadmission use of antidiabetic medications and mortality among patients with COVID-19 having type 2 diabetes: A meta-analysis Association Between Anti-diabetic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis Efficacy of glimepiride on insulin resistance, adipocytokines, and atherosclerosis Adiponectin and Creactive protein in obesity, type 2 diabetes, and monodrug therapy Immune Signature of COVID-19: In-Depth Reasons and Consequences of the Cytokine Storm Diabetes medications: Impact on inflammation and wound healing NLRP3 inflammasome inhibitor glyburide expedites diabetic-induced impaired fracture healing Major complications have an impact on total annual medical cost of diabetes: results of a database analysis None.