Metformin in COVID-19: Is There a Role Beyond Glycemic Control?

Context: The coronavirus disease 2019 (COVID-19) pandemic is still a cause of worldwide health concern. Diabetes and its associated comorbidities are risk factors for mortality and morbidity in COVID-19. Selecting the right antidiabetic drug to achieve optimal glycemic control might mitigate some of the negative impacts of diabetes. Metformin continues to be the most widely administered antidiabetic agent. There is evidence of its beneficial outcome in COVID-19 independent of its glucose-lowering effect. Evidence Acquisition: A thorough literature search was conducted in PubMed, Google Scholar, Scopus, and Web of Science to identify studies investigating metformin in COVID-19. Result(s): Several overlapping mechanisms have been proposed to explain its antiviral properties. It could bring about conformational changes in the angiotensin-converting enzyme-2 receptor and decrease viral entry. The effects on the mammalian target of the rapamycin pathway and cellular pH have been proposed to reduce viral protein synthesis and replication. The immunomodulatory effects of metformin might counter the detrimental effects of hyperinflammation associated with COVID-19. Conclusion(s): These findings call for broader metformin usage to manage hyperglycemia in COVID-19.Copyright © 2023, International Journal of Endocrinology and Metabolism.

Antidiabetic treatment and COVID-19 Outcomes: A population-based cohort study in primary health care in Catalonia during the first wave of the pandemic.

AIMS: To analyse if antidiabetic treatment was associated with better COVID-19 outcomes in type 2 diabetic patients, measured by hospital admission and mortality rates as severe outcomes. METHODS: Cohort study including COVID-19 patients registered in the Primary Care electronic records, in March-June 2020, comparing exposed to metformin in monotherapy with exposed to any other antidiabetic. DATA SOURCE: SIDIAP (Information System for Research in Primary Care), which captures clinical information of 5,8 million people from Catalonia, Spain. RESULTS: We included 31,006 diabetic patients infected with COVID-19, 43.7% previously exposed to metformin, 45.5% of them in monotherapy. 16.4% were admitted to hospital and 15.1% died. Users of insulin in monotherapy (OR 1.29, 95% CI 1.11-1.50), combined with metformin (OR 1.38, 1.13-1.69) or IDPP4 alone (OR 1.29, 1.03-1.63) had higher risk of severe outcomes than those in metformin monotherapy. Users of any insulin (OR 1.61, 1.32-1.97) or combined with metformin (OR 1.69, 1.30-2.20) had a higher risk of mortality. CONCLUSIONS: Patients receiving metformin monotherapy in our study showed a lower risk of hospitalization and death in comparison to those treated with other frequent antidiabetic agents. We cannot distinguish if better outcomes are related with the antidiabetic therapy or with other factors, such as metabolic control or interventions applied during the hospital admission.

Considerations for management of patients with diabetes mellitus and acute COVID-19.

Diabetes mellitus (DM) is an independent risk factor for admission to intensive care unit and death in patients with coronavirus disease 2019 (COVID-19). On the other hand, medications used in the management of COVID-19 are potentially associated with increases in blood glucose levels and a higher incidence of infections. Accordingly, care of patients with DM and acute COVID-19 requires careful consideration of both diseases. Hyperglycemia and hypoglycemia are associated with adverse outcomes and therefore frequent measurement of blood glucose levels and a basal-bolus insulin regimen are required in most patients. Regarding the management of COVID-19, dexamethasone increases blood glucose levels and might also increase the risk for infections. On the other hand, limited data suggest that antiviral and immunomodulatory agents used in COVID-19 are not strongly associated with higher incidence of infections in this population. As knowledge evolves in this field, optimization of the management of both DM and COVID-19 will hopefully improve the outcome of these patients.

The Association Between Antidiabetic Agents and Clinical Outcomes of COVID-19 Patients With Diabetes: A Bayesian Network Meta-Analysis.

Aims: This study aimed to assess the impact of different antidiabetic agents on individuals with diabetes and COVID-19. Methods: We searched PubMed, Web of Science, Embase, and Cochrane Library databases from inception to October 31, 2021 and included seven antidiabetic agents. The data were pooled via traditional pairwise meta-analysis and Bayesian network meta-analysis. Results: The pairwise meta-analysis included 35 studies. Metformin (odds ratio (OR), 0.74; P=0.001), dipeptidyl peptidase-4 inhibitors (DPP4i) (OR, 0.88; P=0.04), sodium-glucose cotransporter-2 inhibitors (SGLT2i) (OR, 0.82; P=0.001), and glucagon-like peptide-1 receptor agonists (GLP1RA) (OR, 0.91; P=0.02) treatment were associated with lower COVID-19 mortality in individuals with diabetes compared to respective non-users. However, insulin treatment resulted in higher mortality (OR, 1.8; P=0.001). Mortality did not significantly differ in sulfonylurea (OR, 0.97; P=0.56) and thiazolidinediones (TZDs) (OR, 1.00; P=0.96) users. Furthermore, due to limited data, we analyzed five antidiabetic agents (metformin, DPP4i, sulfonylurea, insulin, and SGLT2i) and found no association between them and severe disease risk (all P>0.05). The Bayesian network meta-analysis included 18 studies. GLP1RA and SGLT2i had the highest first and second rank probability (67.3% and 62.5%, respectively). Insulin showed the maximum probability of ranking seventh (97.0%). Metformin had the third and fourth highest rank probability of 44.8% and 38.9%, respectively. Meanwhile, DPP4i had the fifth-highest rank probability of 42.4%, followed by sulfonylurea at 45.1%. Conclusion: Metformin, DPP4i, SGLT2i, and GLP1RA treatments were highly possible to reduced COVID-19 mortality risk in individuals with diabetes, while insulin might be related to increased mortality risk. Sulfonylurea and TZDs treatments were not associated with mortality. None of the antidiabetic agents studied were associated with the risk of severe disease. Additionally, GLP1RA probably had the most significant protective effect against death, followed by SGLT2i and metformin. Systematic Review Registration: PROSPERO (CRD42021288200).

Careful use to minimize adverse events of oral antidiabetic medications in the elderly.

INTRODUCTION: An increasing number of older patients has type 2 diabetes treated with different oral antidiabetic agents whose safety may raise concern considering some particularities of a heterogeneous elderly population. AREAS COVERED: This article discusses some characteristics of older patients that could increase the risk of adverse events, with a focus on hypoglycemia. It describes the most frequent and/or severe complications reported in the elderly in both randomized controlled trials and observational studies with metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium-glucose cotransporter type 2 inhibitors (gliflozins). EXPERT OPINION: Old patients may present comorbidities (renal impairment, vascular disease, heart failure, risk of dehydration, osteoporosis, cognitive dysfunction) that could increase the risk of severe adverse events. Sulfonylureas (and meglitinides) induce hypoglycemia, which may be associated with falls/fractures and cardiovascular events. Medications lacking hypoglycemia should be preferred. Gliptins appear to have the best tolerance/safety profile whereas gliflozins exert a cardiorenal protection. However, data are lacking in very old or frailty old patients so that caution and appropriate supervision of such patients are required. Taking advantage of a large choice of pharmacotherapies, personalized treatment is recommended based upon both drug safety profiles and old patient individual characteristics.

Association of clinical characteristics, antidiabetic and cardiovascular agents with diabetes mellitus and COVID-19: a 7-month follow-up cohort study.

BACKGROUND: The prognostic factors of long-term outcomes in hospitalized patients with diabetes mellitus and COVID-19 are lacking. METHODS: In this retrospective cohort study, we evaluated patients aged ≥ 18-years-old with the COVID-19 diagnosis who were hospitalized between Feb 20 and Oct 29, 2020, in the Sina Hospital, Tehran, Iran. 1323 patients with COVID-19 entered in the final analysis, of whom 393 (29.7%) patients had diabetes. We followed up patients for incurring in-hospital death, severe COVID-19, in-hospital complications, and 7-month all-cause mortality. By doing univariate analysis, variables with unadjusted P-value < 0.1 in univariate analyses were regarded as the confounders to include in the logistic regression models. We made adjustments for possible clinical (model 1) and both clinical and laboratory (model 2) confounders. RESULTS: After multivariable regression, it was revealed that preadmission use of sulfonylureas was associated with a borderline increased risk of severity in both models [model 1, OR (95% CI):1.83 (0.91-3.71), P-value: 0.092; model 2, 2.05 (0.87-4.79), P-value: 0.099] and major adverse events (MAE: each of the severe COVID-19, multi-organ damage, or in-hospital mortality) in model 1 [OR (95% CI): 1.86 (0.90-3.87), P-value: 0.094]. Preadmission use of ACEIs/ARBs was associated with borderline increased risk of MAE in the only model 1 [OR (95% CI):1.83 (0.96-3.48), P-value: 0.066]. CONCLUSIONS: Preadmission use of sulfonylureas and ACEIs/ARBs were associated with borderline increased risk of in-hospital adverse outcomes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00901-4.

Blood Glucose Control Strategy for Type 2 Diabetes Patients With COVID-19.

Since December 2019, coronavirus disease 2019 (COVID-19) caused by a novel coronavirus has spread all over the world affecting tens of millions of people. Another pandemic affecting the modern world, type 2 diabetes mellitus is among the major risk factors for mortality from COVID-19. Current evidence, while limited, suggests that proper blood glucose control may help prevent exacerbation of COVID-19 even in patients with type 2 diabetes mellitus. Under current circumstances where the magic bullet for the disease remains unavailable, it appears that the role of blood glucose control cannot be stressed too much. In this review the profile of each anti-diabetic agent is discussed in relation to COVID-19.

Mortality Risk of Antidiabetic Agents for Type 2 Diabetes With COVID-19: A Systematic Review and Meta-Analysis.

Aims: We conducted a systematic review and meta-analysis to assess various antidiabetic agents' association with mortality in patients with type 2 diabetes (T2DM) who have coronavirus disease 2019 (COVID-19). Methods: We performed comprehensive literature retrieval from the date of inception until February 2, 2021, in medical databases (PubMed, Web of Science, Embase, and Cochrane Library), regarding mortality outcomes in patients with T2DM who have COVID-19. Pooled OR and 95% CI data were used to assess relationships between antidiabetic agents and mortality. Results: Eighteen studies with 17,338 patients were included in the meta-analysis. Metformin (pooled OR, 0.69; P=0.001) and sulfonylurea (pooled OR, 0.80; P=0.016) were associated with lower mortality risk in patients with T2DM who had COVID-19. However, patients with T2DM who had COVID-19 and received insulin exhibited greater mortality (pooled OR, 2.20; P=0.002). Mortality did not significantly differ (pooled OR, 0.72; P=0.057) between DPP-4 inhibitor users and non-users. Conclusions: Metformin and sulfonylurea could be associated with reduced mortality risk in patients with T2DM who have COVID-19. Furthermore, insulin use could be associated with greater mortality, while DPP-4 inhibitor use could not be. The effects of antidiabetic agents in patients with T2DM who have COVID-19 require further exploration. Systematic Review Registration: PROSPERO (identifier, CRD42021242898).

Perspectives of Antidiabetic Drugs in Diabetes With Coronavirus Infections.

Diabetes mellitus (DM) increases the risk of viral infections especially during the period of poor glycemic controls. Emerging evidence has reported that DM is one of the most common comorbidities in the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, also referred to as COVID-19. Moreover, the management and therapy are complex for individuals with diabetes who are acutely unwell with suspected or confirmed COVID-19. Here, we review the role of antidiabetic agents, mainly including insulin, metformin, pioglitazone, dipeptidyl peptidase-4 (DPP4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists in DM patients with coronavirus infection, addressing the clinical therapeutic choices for these subjects.

The potential effects of clinical antidiabetic agents on SARS-CoV-2.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is currently posing significant threats to public health worldwide. It is notable that a substantial proportion of patients with sever COVID-19 have coexisting diabetic conditions, indicating the progression and outcome of COVID-19 may relate to diabetes. However, it is still unclear whether diabetic treatment principles can be used for the treatment of COVID-19. METHODS: We conducted a computational approach to screen all commonly used clinical oral hypoglycemic drugs to identify the potential inhibitors for the main protease (Mpro ) of SARS-CoV-2, which is one of the key drug targets for anti-COVID-19 drug discovery. RESULTS: Six antidiabetic drugs with docking scores higher than 8.0 (cutoff value), including repaglinide, canagliflozin, glipizide, gliquidone, glimepiride, and linagliptin, were predicted as the promising inhibitors of Mpro . Interestingly, repaglinide, one of the six antidiabetic drugs with the highest docking score for Mpro , was similar to a previously predicted active molecule nelfinavir, which is a potential anti-HIV and anti-COVID-19 drug. Moreover, we found repaglinide shared similar docking pose and pharmacophores with a reported ligand (N3 inhibitor) and nelfinavir, demonstrating that repaglinide would interact with Mpro in a similar way. CONCLUSION: These results indicated that these six antidiabetic drugs may have an extra effect on the treatment of COVID-19, although further studies are necessary to confirm these findings.

COVID-19 and Diabetes Mellitus: May Old Anti-diabetic Agents Become the New Philosopher's Stone?

Corona virus infectious disease (COVID-19) is a new pandemic. In subjects with diabetes mellitus, infection may be more frequent and severe. We discuss the potential contribution of two traditional oral antidiabetic agents, metformin and pioglitazone, to the improvement of liver injury in COVID-19. Clearly, further experience is needed to shed light on these hypotheses.