Hypoglycemic Therapy and the Course of Post-Covid Syndrome, is There a Connection?

Diabetes mellitus (both type 1 and type 2) is considered one of the risk factors for severe COVID-19 and death from this infection. Past infection with COVID-19 leads to deterioration in the control of existing diabetes mellitus, progression of pre-diabetes to diabetes, an increase in the number of new cases of diabetes and an increase in the proportion of glucocorticoid-induced diabetes, which significantly aggravates the course of post-COVID syndrome for this category of patients. Antihyperglycemic drugs may influence the pathogenesis of COVID-19, which may be of relevance for the treatment of patients with type 2 diabetes mellitus and post-COVID syndrome. The review also presents our own data on the effect of various regimens of oral hypoglycemic agents on post-COVID syndrome in people with type 2 diabetes mellitus. The observation showed that the use of dipeptidyl peptidase-4 inhibitors as part of a treatment strategy in patients with type 2 diabetes mellitus with a past COVID-19 infection was associated with a decrease in the duration and severity of post-COVID symptoms.Copyright © 2023 The Russian Archives of Internal Medicine. All rights reserved.

Association between use of novel glucose-lowering drugs and COVID-19 hospitalization and death in patients with type 2 diabetes: a nationwide registry analysis.

AIMS: Type 2 diabetes (T2DM) in patients with coronavirus disease-19 (COVID-19) is associated with worse prognosis. We separately investigated the associations between the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and the risk of COVID-19 hospitalization and death. METHODS AND RESULTS: Patients with T2DM registered in the Swedish National Patient Registry and alive on 1st February 2020 were included. "Incident severe COVID-19" was defined as the first hospitalization and/or death from COVID-19. A modified Poisson regression approach was applied to a 1:1 propensity score-matched population receiving vs. not receiving SGLT2i, GLP-1 RA and DPP-4i to analyze the associations between their use and I) incident severe COVID-19, II) risk of 30-day mortality in patients hospitalized for COVID-19.Among 344,413 patients, 39,172 (11%) were treated with SGLT2i, 34,290 (10%) with GLP-1 RA and 53,044 (15%) with DPP-4i; 9,538 (2.8%) had incident severe COVID-19 by 15th May 2021. SGLT2i and DPP-4i were associated with a 10% and 11% higher risk of incident severe COVID-19, respectively, whereas there was no association for GLP-1 RA. DPP-4i were also associated with a 10% higher 30-day mortality in patients hospitalized for COVID-19, whereas there was no association for SGLT2i and GLP-1 RA. CONCLUSION: SGLT2i and DPP-4i use was associated with higher risk of incident severe COVID-19. DPP-4i use was associated with higher 30-day mortality in patients with COVID-19, whereas SGLT2i use was not. No increased risk for any outcome was observed with GLP-1 RA.

Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, and Sodium-Glucose Cotransporter-2 Inhibitors and COVID-19 Outcomes.

PURPOSE: It has been reported that dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a role in modulation of inflammation associated with coronavirus disease 2019 (COVID-19). This study assessed the effect of these drug classes on COVID-19-related outcomes. METHODS: Using a COVID-19 linkable administrative database, we selected patients aged ≥40 years with at least 2 prescriptions of DPP-4i, GLP-1 RA, or SGLT-2i or any other antihyperglycemic drug and a diagnosis of COVID-19 from February 15, 2020, to March 15, 2021. Adjusted odds ratios (ORs) with 95% CIs were used to calculate the association between treatments and all-cause and in-hospital mortality and COVID-19-related hospitalization. A sensitivity analysis was performed by using inverse probability treatment weighting. FINDINGS: Overall, 32,853 subjects were included in the analysis. Multivariable models showed a reduction of the risk for COVID-19 outcomes for users of DPP-4i, GLP-1 RA, and SGLT-2i compared with nonusers, although statistical significance was reached only in DPP-4i users for total mortality (OR, 0.89; 95% CI, 0.82-0.97). The sensitivity analysis confirmed the main results reaching a significant reduction for hospital admission in GLP-1 RA users and in-hospital mortality in SGLT-2i users compared with nonusers. IMPLICATIONS: This study found a beneficial effect in the risk reduction of COVID-19 total mortality in DPP-4i users compared with nonusers. A positive trend was also observed in users of GLP-1 RA and SGLT-2i compared with nonusers. Randomized clinical trials are needed to confirm the effect of these drug classes as potential therapy for the treatment of COVID-19.

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

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.

Does DPP-4 inhibitor treatment affect the clinical outcomes of COVID-19 in type 2 diabetes mellitus patients?

OBJECTIVE: We aim to investigate whether the use of dipeptidyl peptidase inhibitors (DPP-4i) affects the severity of disease, hospital mortality, and 3-month post-discharge mortality in type 2 diabetes mellitus (T2DM) individuals with coronavirus disease 2019 (COVID-19) infection. METHODS: The study included 217 patients with type 2 diabetes hospitalized due to COVID-19 between March and October 2020. The patients included in the study were divided into two groups those using DPP-4i and those not using DPP-4i. Demographic characteristics, laboratory parameters, accompanying risk factors, concomitant comorbidities, hospital mortality, clinical course, and 3-month post-discharge mortality were compared between the patients who used DPP-4i and those who did not use. RESULTS: The duration of hospitalization was 10.96±9.16 days in the group using DPP-4i, 12.22±9.1 days in the group not using DPP-4i, and when both groups were evaluated together, it was determined as 11.91±9.11 days. The hospitalization periods were similar between DPP-4i users and non-DPP-4i users (p=0.384). The need for mechanical ventilation (p=0.478 OR 0.710 95% confidence interval [CI], 0.274-1.836) and high-flow nasal cannula (p=0.457, OR: 0.331, 95% CI: 0.41-2.67) were similar between DPP-4i users and non-users. It was determined that the mortality (p=0.208, OR: 0.409, 95% CI: 0.117-1.429) and 3-month post-discharge mortality (p=0.383) were similar in the group using DPP-4i and those not using DPP-4i. CONCLUSION: This study demonstrated that the use of DPP-4i by patients with T2DM in catching COVID-19 does not affect the mortality due to COVID-19, the severity of COVID-19 disease, and 3-month post-discharge mortality.

Screening of potential inhibitors of COVID-19 with repurposing approach via molecular docking.

SARS-CoV-2 (COVID-19) is the causative organism for a pandemic disease with a high rate of infectivity and mortality. In this study, we aimed to assess the affinity between several available small molecule and proteins, including Abl kinase inhibitors, Janus kinase inhibitor, dipeptidyl peptidase 4 inhibitors, RNA-dependent RNA polymerase inhibitors, and Papain-like protease inhibitors, using binding simulation, to test whether they may be effective in inhibiting COVID-19 infection through several mechanisms. The efficiency of inhibitors was evaluated based on docking scores using AutoDock Vina software. Strong ligand-protein interactions were predicted among some of these drugs, that included: Imatinib, Remdesivir, and Telaprevir, and this may render these compounds promising candidates. Some candidate drugs might be efficient in disease control as potential inhibitors or lead compounds against the SARS-CoV-2. It is also worth highlighting the powerful immunomodulatory role of other drugs, such as Abivertinib that inhibits pro-inflammatory cytokine production associated with cytokine release syndrome (CRS) and the progression of COVID-19 infection. The potential role of other Abl kinase inhibitors, including Imatinib in reducing SARS-CoV and MERS-CoV viral titers, immune regulatory function and the development of acute respiratory distress syndrome (ARDS), indicate that this drug may be useful for COVID-19, as the SARS-CoV-2 genome is similar to SARS-CoV.

Use of Novel Antidiabetic Agents in Patients with Type 2 Diabetes and COVID-19: A Critical Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). The latter is a pandemic that has the potential of developing into a severe illness manifesting as systemic inflammatory response syndrome, acute respiratory distress syndrome, multi-organ involvement and shock. In addition, advanced age and male sex and certain underlying health conditions, like type 2 diabetes mellitus (T2DM), predispose to a higher risk of greater COVID-19 severity and mortality. This calls for an urgent identification of antidiabetic agents associated with more favourable COVID-19 outcomes among patients with T2DM, as well as recognition of their potential underlying mechanisms. It is crucial that individuals with T2DM be kept under very stringent glycaemic control in order to avoid developing various cardiovascular, renal and metabolic complications associated with more severe forms of COVID-19 that lead to increased mortality. The use of novel antidiabetic agents dipeptidyl peptidase 4 inhibitors (DPP4i), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) in subjects with T2DM may have beneficial effects on COVID-19 outcomes. However, relevant studies either show inconsistent results (DPP4i) or are still too few (SGLT2i and GLP-1RAs). Further research is therefore needed to assess the impact of these agents on COVID-19 outcomes.

Dipeptidyl peptidase-4 inhibitor use and mortality in COVID-19 patients with diabetes mellitus: an updated systematic review and meta-analysis.

BACKGROUND: Few observational studies have shown a beneficial effect of dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with coronavirus disease 2019 (COVID-19), although results are not consistent. The present systematic review and meta-analysis was undertaken to provide a precise summary of the effect of DPP4i use (preadmission or in-hospital) and mortality in COVID-19 patients with diabetes mellitus (DM). METHODS: PubMed and Google Scholar databases were systematically searched using appropriate keywords to 4 January 2021, to identify observational studies reporting mortality in COVID-19 patients with DM using DPP4i versus those not using DPP4i. Preadmission and in-hospital use of DPP4i were considered. Study quality was assessed using the Newcastle-Ottawa Scale. Unadjusted and adjusted pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Subgroup analysis was performed for studies reporting preadmission and in-hospital use of DPP4i. RESULTS: We identified nine observational studies of high quality pooling data retrieved from 7008 COVID-19 patients with DM. The pooled analysis of unadjusted and adjusted data did not show any significant association between DPP4i use and mortality in COVID-19 patients with DM. However, on subgroup analysis, we found that in-hospital (and not preadmission) DPP4i use was associated with reduced mortality (unadjusted OR 0.37, 95% CI 0.23, 0.58, p < 0.0001, I 2 = 0% and adjusted OR 0.27, 95% CI 0.13, 0.55, p = 0.0003, I 2 = 12%). CONCLUSIONS: In-hospital use of DPP4i is associated with a significant reduction in COVID-19 mortality. Hence, it would be prudent to initiate or continue DPP4i in COVID-19 patients with DM if not contraindicated.

Anti-inflammatory properties of antidiabetic drugs: A "promised land" in the COVID-19 era?

Inflammation is implicated in the development and severity of the coronavirus disease 2019 (COVID-19), as well as in the pathophysiology of diabetes. Diabetes, especially when uncontrolled, is also recognized as an important risk factor for COVID-19 morbidity and mortality. Furthermore, certain inflammatory markers [i.e. C-reactive protein (CRP), interleukin-6 (IL-6) and ferritin] were reported as strong predictors of worse outcomes in COVID-19 positive patients. The same biomarkers have been associated with poor glycemic control. Therefore, achieving euglycemia in patients with diabetes is even more important in the era of the COVID-19 pandemic. Based on the above, it is clinically interesting to elucidate whether antidiabetic drugs may reduce inflammation, thus possibly minimizing the risk for COVID-19 development and severity. The present narrative review discusses the potential anti-inflammatory properties of certain antidiabetic drugs (i.e. metformin, pioglitazone, sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin, liraglutide, dulaglutide, exenatide, lixisenatide, semaglutide, empagliflozin, dapagliflozin, canagliflozin), with a focus on CRP, IL-6 and ferritin.