DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature.

DPP-4 inhibition is an interesting line of therapy for treating Type 2 Diabetes Mellitus (T2DM) and is based on promoting the incretin effect. Here, the authors have presented a brief appraisal of DPP-4 inhibitors, their modes of action, and the clinical efficiency of currently available drugs based on DPP-4 inhibitors. The safety profiles as well as future directions including their potential application in improving COVID-19 patient outcomes have also been discussed in detail. This review also highlights the existing queries and evidence gaps in DPP-4 inhibitor research. Authors have concluded that the excitement surrounding DPP-4 inhibitors is justified because in addition to controlling blood glucose level, they are good at managing risk factors associated with diabetes.

The potential effects of DPP-4 inhibitors on cardiovascular system in COVID-19 patients.

With the outbreak of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the public healthcare systems are facing great challenges. Coronavirus disease 2019 (COVID-19) could develop into severe pneumonia, acute respiratory distress syndrome and multi-organ failure. Remarkably, in addition to the respiratory symptoms, some COVID-19 patients also suffer from cardiovascular injuries. Dipeptidyl peptidase-4 (DPP-4) is a ubiquitous glycoprotein which could act both as a cell membrane-bound protein and a soluble enzymatic protein after cleavage and release into the circulation. Despite angiotensin-converting enzyme 2 (ACE2), the recently recognized receptor of SARS-CoV and SARS-CoV-2, which facilitated their entries into the host, DPP-4 has been identified as the receptor of middle east respiratory syndrome coronavirus (MERS-CoV). In the current review, we discussed the potential roles of DPP-4 in COVID-19 and the possible effects of DPP-4 inhibitors on cardiovascular system in patients with COVID-19.

DPP4 inhibitors: Could they be one of the solutions for COVID-19 patients with prediabetes?

Recent reports suggest that prediabetes is a risk factor for developing severe COVID-19 complications through underlying mechanisms involving undiagnosed sub-clinical inflammation. However, we remain without a clinical approach for managing COVID-19 in prediabetic cases. The subclinical inflammation in prediabetes is associated with elevated DPP4 levels and activity. DPP4 has pleiotropic actions, including glycaemia regulation and immuno-modulation. Recently, DPP4 has been recognised as a co-receptor for COVID-19 for entering host cells. In addition to improving glycaemia, DPP4 inhibition is associated with reduced inflammation. In this submission, we explore the potential use of DPP4 inhibitors as therapeutic agents for prediabetic patients in managing the deleterious effects of COVID-19. DPP4 inhibitors (gliptins) such as linagliptin and sitagliptin have therapeutic effects which have been shown to extend beyond glycaemic control with no risk of hypoglycaemia. By the nature of their mechanism of action, gliptins are not associated with hypoglycaemia, unlike their anti-glycaemic counterparts, as they mainly target postprandial glycaemia. Moreover, DPP4 inhibitors may represent a safer option for prediabetic individuals in managing prediabetes either as a prophylactic or curative treatment for COVID-19. We envisage that beyond improved glycaemic control, the use of DPP4 inhibitors would also alleviate the cytokine storm, resulting in a reduction in the severity of COVID-19 symptoms and consequently reducing the morbidity and mortality in prediabetic COVID-19 patients.

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

BACKGROUND: Patients with diabetes are more likely to suffer COVID-19 complications. Using noninsulin antihyperglycemic medications (AGMs) during COVID-19 infection has proved challenging. In this study, we evaluate different noninsulin AGMs in patients with COVID-19. METHODS: We searched Medline, Embase, Web of Science, and Cochrane on 24 January 2022. We used the following keywords (COVID-19) AND (diabetes mellitus) AND (antihyperglycemic agent). The inclusion criteria were studies reporting one or more of the outcomes. We excluded non-English articles, case reports, and literature reviews. Study outcomes were mortality, hospitalization, and intensive care unit (ICU) admission. RESULTS: The use of metformin rather than other glucose-lowering medications was associated with statistically significant lower mortality (risk ratio [RR]: 0.60, 95% confidence interval [CI]: 0.47, 0.77, p < .001). Dipeptidyl peptidase-4 inhibitor (DPP-4i) use was associated with statistically significantly higher hospitalization risk (RR: 1.44, 95% CI: 1.23, 1.68, p < .001) and higher risk of ICU admissions and/or mechanical ventilation vs nonusers (RR: 1.24, 95% CI: 1.04, 1.48, p < .02). There was a statistically significant decrease in hospitalization for SGLT-2i users vs nonusers (RR: 0.89, 95% CI: 0.84-0.95, p < .001). Glucagon-like peptide-1 receptor agonist (GLP-1RA) use was associated with a statistically significant decrease in mortality (RR: 0.56, 95% CI: 0.42, 073, p < 0.001), ICU admission, and/or mechanical ventilation (RR: 0.79, 95% CI: 0.69-0.89, p < .001), and hospitalization (RR: 0.73, 95% CI: 0.54, 0.98, p = .04). CONCLUSIONS: AGM use was not associated with increased mortality. However, metformin and GLP-1RA use reduced mortality risk statistically significantly. DPP-4i use was associated with a statistically significant increase in the risk of hospitalization and admission to the ICU.

Drug-Disease Severity and Target-Disease Severity Interaction Networks in COVID-19 Patients.

Drug interactions with other drugs are a well-known phenomenon. Similarly, however, pre-existing drug therapy can alter the course of diseases for which it has not been prescribed. We performed network analysis on drugs and their respective targets to investigate whether there are drugs or targets with protective effects in COVID-19, making them candidates for repurposing. These networks of drug-disease interactions (DDSIs) and target-disease interactions (TDSIs) revealed a greater share of patients with diabetes and cardiac co-morbidities in the non-severe cohort treated with dipeptidyl peptidase-4 (DPP4) inhibitors. A possible protective effect of DPP4 inhibitors is also plausible on pathophysiological grounds, and our results support repositioning efforts of DPP4 inhibitors against SARS-CoV-2. At target level, we observed that the target location might have an influence on disease progression. This could potentially be attributed to disruption of functional membrane micro-domains (lipid rafts), which in turn could decrease viral entry and thus disease severity.

IMPACT OF ANTIDIABETIC DRUGS ON RISK AND OUTCOME OF COVID-19 INFECTION: A REVIEW

Based on many reports, an unmistakable link probably exists between diabetes mellitus and COVID-19. A major predisposing factor determining severity and mortality of COVID-19 is diabetes mellitus, diabetic patients were shown to be at higher risk for developing severe COVID-19 disease than non-diabetics;many recent studies reported a striking prevalence of DM in those diagnosed with COVID-19. Accordingly, antidiabetic drugs can possibly impact the clinical course and / or the outcome of this infection, either by alleviating diabetes-associated symptoms, minimizing its complications, or by mitigating or aggravating COVID-19 disease by effects independent from their direct antidiabetic effects. Several antidiabetic drug classes were shown to have varying effects, like blocking viral entry to cells, as well as having immunomodulatory, anti-inflammatory, antifibrotic, or cardioprotective effects;such effects could prove beneficial for COVID-19 patients. On the other hand, some antidiabetic agents may have adverse effects that aggravate patients’ condition like hypoglycemia, fluid retention, increased weight or lactic acidosis, which require special consideration in patient management. Some of the drugs were found in observational studies to either reduce mortality from COVID-19 or pose no harm, but more solid evidence from clinical trials is still lacking. © 2022, University of Defence, Faculty of Military Health Sciences. All rights reserved.

The Roles of Dipeptidyl Peptidase 4 (DPP4) and DPP4 Inhibitors in Different Lung Diseases: New Evidence.

CD26/Dipeptidyl peptidase 4 (DPP4) is a type II transmembrane glycoprotein that is widely expressed in various organs and cells. It can also exist in body fluids in a soluble form. DPP4 participates in various physiological and pathological processes by regulating energy metabolism, inflammation, and immune function. DPP4 inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. More evidence has shown the role of DPP4 in the pathogenesis of lung diseases, since it is highly expressed in the lung parenchyma and the surface of the epithelium, vascular endothelium, and fibroblasts of human bronchi. It is a potential biomarker and therapeutic target for various lung diseases. During the coronavirus disease-19 (COVID-19) global pandemic, DPP4 was found to be an important marker that may play a significant role in disease progression. Some clinical trials on DPP4 inhibitors in COVID-19 are ongoing. DPP4 also affects other infectious respiratory diseases such as Middle East respiratory syndrome and non-infectious lung diseases such as pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), and asthma. This review aims to summarize the roles of DPP4 and its inhibitors in infectious lung diseases and non-infectious diseases to provide new insights for clinical physicians.

Pleiotropic Benefits of DPP-4 Inhibitors Beyond Glycemic Control.

Dipeptidyl peptidase (DPP)-4 inhibitors are oral anti-diabetic medications that block the activity of the ubiquitous enzyme DPP-4. Inhibition of this enzyme increases the level of circulating active glucagon-like peptide (GLP)-1 secreted from L-cells in the small intestine. GLP-1 increases the glucose level, dependent on insulin secretion from pancreatic ß-cells; it also decreases the abnormally increased level of glucagon, eventually decreasing the blood glucose level in patients with type 2 diabetes. DPP-4 is involved in many physiological processes other than the degradation of GLP-1. Therefore, the inhibition of DPP-4 may have numerous effects beyond glucose control. In this article, we review the pleiotropic effects of DPP-4 inhibitors beyond glucose control, including their strong beneficial effects on the stress induced accelerated senescence of vascular cells, and the possible clinical implications of these effects.

Association Between Anti-diabetic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: During the current Coronavirus Disease 2019 (COVID-19) pandemic, patients with diabetes face disproportionately more. This study was performed to clarify anti-inflammatory effects of anti-diabetic agents on COVID-19 in patients with diabetes. METHODS AND RESULTS: Relevant literature was searched on 15 databases up to November 14, 2020 and was updated on April 13, 2021. The pooled ORs along with 95% CIs were calculated to evaluate combined effects. 31 studies with 66,914 patients were included in qualitative and quantitative synthesis. Meta-analysis showed that metformin was associated with a statistically significant lower mortality (pooled OR = 0.62, 95% CI, 0.50-0.76, p = 0.000) and poor composite outcomes (pooled OR = 0.83, 95% CI, 0.71-0.97, p = 0.022) in diabetic patients with COVID-19. Significance of slight lower mortality remained in sulfonylurea/glinides (pooled OR = 0.93, 95% CI, 0.89-0.98, p = 0.004), but of poor composite outcomes was not (pooled OR = 1.48, 95% CI, 0.61-3.60, p = 0.384). Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were associated with statistically non-significant lower mortality (pooled OR = 0.95, 95% CI, 0.72-1.26, p = 0.739) or poor composite outcomes (pooled OR = 1.27, 95% CI, 0.91-1.77, p = 0.162) of COVID-19 in diabetic patients. CONCLUSION: Metformin might be beneficial in decreasing mortality and poor composite outcomes in diabetic patients infected with SARS-CoV-2. DPP-4 inhibitors, sulfonylurea/glinides, SGLT-2 inhibitors, and GLP-1RA would not seem to be adverse. There was insufficient evidence to conclude effects of other anti-diabetic agents. Limited by retrospective characteristics, with relative weak capability to verify causality, more prospective studies, especially RCTs are needed. REGISTRATION NUMBER: PROSPERO-CRD42020221951.

Treatment with a DPP-4 inhibitor at time of hospital admission for COVID-19 is not associated with improved clinical outcomes: data from the COVID-PREDICT cohort study in The Netherlands.

Purpose: Inhibition of dipeptidyl peptidase (DPP-)4 could reduce coronavirus disease 2019 (COVID-19) severity by reducing inflammation and enhancing tissue repair beyond glucose lowering. We aimed to assess this in a prospective cohort study. Methods: We studied in 565 patients with type 2 diabetes in the CovidPredict Clinical Course Cohort whether use of a DPP-4 inhibitor prior to hospital admission due to COVID-19 was associated with improved clinical outcomes. Using crude analyses and propensity score matching (on age, sex and BMI), 28 patients using a DPP-4 inhibitor were identified and compared to non-users. Results: No differences were found in the primary outcome mortality (matched-analysis = odds-ratio: 0,94 [95% confidence interval: 0,69 - 1,28], p-value: 0,689) or any of the secondary outcomes (ICU admission, invasive ventilation, thrombotic events or infectious complications). Additional analyses comparing users of DPP-4 inhibitors with subgroups of non-users (subgroup 1: users of metformin and sulphonylurea; subgroup 2: users of any insulin combination), allowing to correct for diabetes severity, did not yield different results. Conclusions: We conclude that outpatient use of a DPP-4 inhibitor does not affect the clinical outcomes of patients with type 2 diabetes who are hospitalized because of COVID-19 infection.

[Diabetes and COVID-19]. / Diabète et COVID-19.

According to previous reports, diabetes seems to be associated with serious clinical events due to COVID-19. But is diabetes per se a risk factor of being infected by the virus? We discuss these points. Data about the antidiabetic drugs are scarce. Dipeptidylpeptidase-4 (DPP-4) is found as both a cell surface protein ubiquitously expressed in many tissues and as a soluble molecule found in serum/plasma, fluids. DPP-4 is involved in infection of cells by some viruses. We relate data about the use of DPP-4 inhibitors in diabetic patients. We conclude relating French and international recommendations in people with diabetes.

Cytokine storm modulation in COVID-19: a proposed role for vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i).

A dysregulated immune response characterized by the hyperproduction of several pro-inflammatory cytokines (a.k.a. 'cytokine storm') plays a central role in the pathophysiology of severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this Perspective article we discuss the evidence for synergistic anti-inflammatory and immunomodulatory properties exerted by vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors, the latter being a class of antihyperglycemic agents used for the treatment of Type 2 diabetes, which have also been reported as immunomodulators. Then, we provide the rationale for investigation of vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i) as an immunomodulation strategy to ratchet down the virulence of SARS-CoV-2, prevent disease progression and modulate the cytokine storm in COVID-19.

Lay abstract The so-called 'cytokine storm' that drives the hyperproduction of pro-inflammatory mediators, plays a central role in the pathophysiology of severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vitamin D has increasingly been shown to play anti-inflammatory and immunomodulatory properties beyond its role in the regulation of bone homeostasis. Similarly, dipeptidyl peptidase-4 inhibitors (DPP-4i) ­ a class of antihyperglycemic agents used for the treatment of Type 2 diabetes ­ have been reported as immunomodulators regardless of their glucose-lowering properties. We, therefore, discuss the role of vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i) as a potential immunomodulation strategy to prevent the development and/or halt the progression of the COVID-19-induced cytokine storm, particularly in patients with diabetes and cardiovascular disease.

No significant association between dipeptidyl peptidase-4 inhibitors and adverse outcomes of COVID-19.

BACKGROUND: Dipeptidyl peptidase-4 (DPP4) is commonly targeted to achieve glycemic control and has potent anti-inflammatory and immunoregulatory effects. Recent structural analyses indicated a potential tight interaction between DPP4 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raising a promising hypothesis that DPP4 inhibitor (DPP4i) drugs might be an optimal strategy for treating coronavirus disease 2019 (COVID-19) among patients with diabetes. However, there has been no direct clinical evidence illuminating the associations between DPP4i use and COVID-19 outcomes. AIM: To illuminate the associations between DPP4i usage and the adverse outcomes of COVID-19. METHODS: We conducted a multicenter, retrospective analysis including 2563 patients with type 2 diabetes who were hospitalized due to COVID-19 at 16 hospitals in Hubei Province, China. After excluding ineligible individuals, 142 patients who received DPP4i drugs and 1115 patients who received non-DPP4i oral anti-diabetic drugs were included in the subsequent analysis. We performed a strict propensity score matching (PSM) analysis where age, sex, comorbidities, number of oral hypoglycemic agents, heart rate, blood pressure, pulse oxygen saturation (SpO2) < 95%, CT diagnosed bilateral lung lesions, laboratory indicators, and proportion of insulin usage were matched. Finally, 111 participants treated with DPP4i drugs were successfully matched to 333 non-DPP4i users. Then, a linear logistic model and mixed-effect Cox model were applied to analyze the associations between in-hospital DPP4i use and adverse outcomes of COVID-19. RESULTS: After rigorous matching and further adjustments for imbalanced variables in the linear logistic model and Cox adjusted model, we found that there was no significant association between in-hospital DPP4i use (DPP4i group) and 28-d all-cause mortality (adjusted hazard ratio = 0.44, 95%CI: 0.09-2.11, P = 0.31). Likewise, the incidences and risks of secondary outcomes, including septic shock, acute respiratory distress syndrome, or acute organ (kidney, liver, and cardiac) injuries, were also comparable between the DPP4i and non-DPP4i groups. The performance of DPP4i agents in achieving glucose control (e.g., the median level of fasting blood glucose and random blood glucose) and inflammatory regulation was approximately equivalent in the DPP4i and non-DPP4i groups. Furthermore, we did not observe substantial side effects such as uncontrolled glycemia or acidosis due to DPP4i application relative to the use of non-DPP4i agents in the study cohort. CONCLUSION: Our findings demonstrated that DPP4i use is not significantly associated with poor outcomes of COVID-19 or other adverse effects of anti-diabetic treatment. The data support the continuation of DPP4i agents for diabetes management in the setting of COVID-19.

Use of DPP4 inhibitors in Italy does not correlate with diabetes prevalence among COVID-19 deaths.

In a nationwide study of 3818 charts from patients with fatal COVID-19, we found that geographical differences in Dipeptidyl peptidase 4 (DPP4) inhibitors use did not correlate with diabetes prevalence among COVID-19 deaths, thus not supporting the hypothesis of a clinically relevant involvement of DPP4 inhibition in COVID-19 development and progression.

DPP-4 Inhibitors in the Prevention/Treatment of Pulmonary Fibrosis, Heart and Kidney Injury Caused by COVID-19-A Therapeutic Approach of Choice in Type 2 Diabetic Patients?

Since the outbreak of SARS-CoV-2 virus more than 12,500,000 cases have been reported worldwide. Patients suffering from diabetes and other comorbidities are particularly susceptible to severe forms of the COVID-19, which might result in chronic complications following recovery. Dipeptidyl peptidase-4 inhibitors exert beneficial effects in prevention/treatment of pulmonary fibrosis, heart, and kidney injury, and since they may be a long-term consequence caused by COVID-19, it is reasonable to expect that DPP-4 inhibitors might be beneficial in alleviating long-term consequences of COVID-19. With that in mind, we would like to voice our concerns over chronic implications following recovery from COVID-19, especially not only in diabetic but also in non-diabetic patients, and to indicate that some preventive measures could be undertaken by application of DPP-4 inhibitors.

Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety.

The COVID-19 pandemic is caused by the severe acute-respiratory-syndrome-coronavirus-2 that uses ACE2 as its receptor. Drugs that raise serum/tissue ACE2 levels include ACE inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) that are commonly used in patients with hypertension, cardiovascular disease and/or diabetes. These comorbidities have adverse outcomes in COVID-19 patients that might result from pharmacotherapy. Increasing ACE2 could potentially increase the risk of infection, severity or mortality in COVID-19 or it might be protective as it forms angiotensin-(1-7) which exhibits anti-inflammatory/anti-oxidative effects and prevents diabetes- and/or hypertension-induced end-organ damage. Thus, there existed clinical uncertainty. Here, we review studies implicating 15 classes of drugs in increasing ACE2 levels in vivo and the available literature on the clinical safety of these drugs in COVID-19 patients. Further, in a re-analysis of clinical data from a meta-analysis of 9 studies, we show that ACEIs/ARBs usage was not associated with an increased risk of all-cause mortality. Literature suggests that ACEIs/ARBs usage generally appears to be clinically safe though their use in severe COVID-19 patients might increase the risk of acute renal injury. For definitive clarity, further clinical and mechanistic studies are needed in assessing the safety of all classes of ACE2 raising medications.

Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19.

AIMS: SARS-CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS-CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS-Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.

In Silico Evaluation of the Effectivity of Approved Protease Inhibitors against the Main Protease of the Novel SARS-CoV-2 Virus.

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.

Potential Benefits and Harms of Novel Antidiabetic Drugs During COVID-19 Crisis.

Patients with diabetes have been reported to have enhanced susceptibility to severe or fatal COVID-19 infections, including a high risk of being admitted to intensive care units with respiratory failure and septic complications. Given the global prevalence of diabetes, affecting over 450 million people worldwide and still on the rise, the emerging COVID-19 crisis poses a serious threat to an extremely large vulnerable population. However, the broad heterogeneity and complexity of this dysmetabolic condition, with reference to etiologic mechanisms, degree of glycemic derangement and comorbid associations, along with the extensive sexual dimorphism in immune responses, can hamper any patient generalization. Even more relevant, and irrespective of glucose-lowering activities, DPP4 inhibitors and GLP1 receptor agonists may have a favorable impact on the modulation of viral entry and overproduction of inflammatory cytokines during COVID-19 infection, although current evidence is limited and not univocal. Conversely, SGLT2 inhibitors may increase the likelihood of COVID-19-related ketoacidosis decompensation among patients with severe insulin deficiency. Mindful of their widespread popularity in the management of diabetes, addressing potential benefits and harms of novel antidiabetic drugs to clinical prognosis at the time of a COVID-19 pandemic deserves careful consideration.