Executive Summary from Expert consensus on effectiveness and safety of iDPP-4 in the treatment of patients with diabetes and COVID-19



# Introduction
The management of patients with diabetes during the COVID-19 pandemic is an aspect that has taken on particular relevance, as diabetic patients with SARS-CoV-2 infection have been found to have a higher risk of a worse prognosis and mortality. The reason for poorer outcomes in patients with diabetes is not yet entirely clear, but it may be due to their reduced immune response to SARS-CoV-2 as a result of chronic hyperglycaemia 2 and/or to the chronic low-grade inflammation associated with diabetes. [bib_ref] Type 2 diabetes and its impact on the immune system, Berbudi [/bib_ref] Some antidiabetic agents (ADA), such as dipeptidyl peptidase-4 (DPP-4) inhibitors, have provoked considerable interest as it has been suggested that they may play a role in reducing the chance of infection with the virus and mitigating the severity of complications associated with COVID-19. [bib_ref] COVID-19 and comorbidities: a role for dipeptidyl peptidase 4 (DPP4) in disease..., Bassendine [/bib_ref] The objective of this review and consensus document is to summarise all of the available data on the potential impact of DPP-4 inhibitors on the clinical outcomes of patients with diabetes during COVID-19, both in diabetic patients treated outside of the hospital setting and in those who required intrahospital management, and to establish recommendations based on the evidence available to date. The full document can be accessed via the following link: Appendix B see additional material.

# Methodology
Several scientific associations and one foundation, all connected with clinical diabetes management After reviewing and selecting the reference materials, conducting an appropriate analysis of the available evidence and agreeing the clinical questions to address, potential recommendations were established by consensus.

## Literature search
A literature search was performed in the PubMed database from December 2019 to February 2021 based on the search strategy outlined in [fig_ref] Table 1: Search strategy approach [/fig_ref].
The results were supplemented with a second manual search. The reviewers carried out the literature selection, data analysis, assessment of the most relevant terms and the quality analysis independently. [fig_ref] Figure 1: PRISMA flow diagram of the article search and selection process [/fig_ref] shows the PRISMA flow diagram of how the article selection process

# Oxford methodology
The quality of the articles selected was assessed using the Oxford Centre for Evidence-Based Medicine (CEBM) Levels of Evidence (Oxford CEBM, 2009).

# Results

## Can diabetes be considered an independent risk factor in the clinical course of patients with sars-cov-2?
The data published to date suggest that diabetes does not appear to increase the risk of COVID-19 infection, but the presence of diabetes in patients with COVID-19 is a risk factor with regard to mortality, disease severity and need for admission to an intensive care unit (ICU) 1 (level of evidence 2a) [fig_ref] Table 2: COVID-19 disease outcomes by presence of diabetes [/fig_ref].
It is not fully clear whether this increase in risk is because of the diabetes per se or because patients with diabetes often have a greater prevalence of other risk factors conducive to a worse prognosis for COVID-19. It has been demonstrated that circulating levels of some cytokines such as interleukin-6 (IL-6) are higher in patients with COVID-19 and diabetes, presenting a worse prognosis than in patients without diabetes. This suggests that in the presence of an underlying proinflammatory environment, diabetes would be an independent risk factor for worse outcomes (level of evidence 5). 5 Expert consensus: Based on this, in diabetes, irrespective of adequate control of comorbidities such as obesity or cardiovascular disease, we would recommend raising awareness of the importance of optimal glycaemic control, caution in premature discontinuation of established therapy and optimisation of antidiabetic therapy, weighing up the possible effects of the drugs on inflammation.
In patients with diabetes and COVID-19, factors to consider may include selecting drugs that guarantee little fluctuation in glycaemic control and have been found to be safe in different scenarios (pre-hospitalisation, hospitalisation, ICU).

## Do patients treated with dpp-4 inhibitors have a higher or lower risk of infection when exposed to sars-cov-2?
Using a modelling-based focus, a recent publication demonstrated that the S1 domain of the SARS-CoV-2 spike glycoprotein might interact with the human DPP-4 membrane, enabling the entry of the virus. [bib_ref] Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein..., Vankadari [/bib_ref] However, a registry conducted in Italy explored the potential association between DPP-4 inhibitors for diabetes and the risk of COVID-19 infection and concluded that DPP-4 inhibitors do not appear to have any protective or harmful effect on COVID-19 incidence 7 (level of evidence 2b), backing up recent data on their neutral role on the incidence of respiratory infections. 8

## Expert consensus:
Although there is a possible interaction between SARS-CoV-2 and DPP-4, the use of DPP-4 inhibitors does not appear to either increase or reduce the risk of SARS-CoV-2 infection.

## Do patients treated with dpp-4 inhibitors have a higher risk of being hospitalised for sars-cov-2?
A case-control study found that the rate of exposure to DPP-4 inhibitors among patients with type 2 diabetes mellitus (T2DM) with SARS-CoV-2 infection hospitalised for COVID-19 was comparable to that of matched patients in the same region or those from the local outpatient clinic. [bib_ref] Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes:..., Fadini [/bib_ref] These data suggest that DPP-4 inhibitors do not increase the risk of hospitalisation in patients with COVID-19, and they are considered a valid therapeutic option for the management of patients with diabetes and symptomatic COVID-19 (level of evidence 4).
Expert consensus: According to the data that currently exist, DPP-4 inhibitors do not increase the risk of hospitalisation in patients with COVID-19. We therefore suggest maintaining treatment with DPP-4 inhibitors in high-or very high-risk epidemiological situations and in mild or moderate COVID-19 disease that does not require hospitalisation.
At a physiological or mechanism-of-action level, is there evidence with regard to the possible advantages that DPP-4 inhibitors might offer in the course of the disease after infection?
DPP-4 inhibitors have anti-adipogenic, anti-platelet and anti-inflammatory effects. Studies have found that starting DPP-4 inhibitors leads to a reduction in cytokine production, and a recent meta-analysis also identified a significant reduction in polymerase chain reaction (PCR) levels after treatment with DPP-4 inhibitors compared to placebo. 10

## Expert consensus:
The anti-inflammatory, anti-platelet and anti-adipogenic effects of DPP-4 inhibitors, as well as the possible modulating role of DPP-4 receptors on virus entry, are potential physiological mechanisms that could contribute to a more favourable clinical course of COVID-19 disease.

## Might the use of dpp-4 inhibitors have an impact on mortality?
The results of the assessment of the studies suggest a beneficial or neutral effect from this group of ADAs (level of evidence 2a). Four meta-analyses also suggest a beneficial or neutral effect of DPP-4 inhibitors on mortality. A cohort study suggests a small (1.07 [1.01---1.13]) but significant increase in mortality, which can be explained by the large sample size and a probable selection bias in being prescribed preferentially to older, more frail patients [fig_ref] Table 3: Outcomes of studies with DPP-4 inhibitors in patients with COVID-19 [/fig_ref]. The possible effect of these drugs might be more apparent in hospitalised patients, as is reflected in the metaanalysis by Pal et al., [bib_ref] Dipeptidyl peptidase-4 inhibitor use and mortality in COVID-19 patients with diabetes mellitus:..., Pal [/bib_ref] which identified nine high-quality observational studies on 7008 patients with diabetes suffering from COVID-19. In the subgroup analysis, the authors observed that intrahospital use of DPP-4 inhibitors was associated with a reduction in mortality (adjusted OR: 0.27; 95% CI: 0.13---0.55; P = .0003).
Given the potential positive impact of DPP-4 inhibitor use, particularly in hospitalised patients, various randomised studies have been launched to clarify this aspect (NCT04365517, NCT04341935 and NCT04371978).

## Expert consensus:
Out-of-hospital use of DPP-4 inhibitors has been found not to increase the risk of mortality in patients with diabetes and COVID-19. Intrahospital use of DPP-4 inhibitors may be associated with a significant reduction in mortality in patients with diabetes and COVID-19. It would therefore be prudent to initiate or continue DPP-4 inhibitors in patients with COVID-19 if not contraindicated.

## Could the use of dpp-4 inhibitors increase the risk of developing severe disease?
The meta-analysis by found that there is no increase in the risk of greater severity (level of evidence 2a). [bib_ref] A meta-analysis on the preadmission use of DPP-4 inhibitors and risk of..., Kow [/bib_ref] Other evidence that DPP-4 inhibitors do not increase patients' severity is found in the study Coronavirus Disease and Diabetes Outcome (CORONADO). In this study, no association was observed between severe clinical course of COVID-19 and treatment with DPP-4 inhibitors prior to admission (OR: 1.01; 95% CI: 0.75---1.34).
However, use of these drugs at hospitalisation appears to significantly reduce the need for mechanical ventilation Expert consensus: Treatment with DPP-4 inhibitors in stable hospitalised patients appears to be a safe treatment option that does not affect the severity of the clinical course of the disease.

## Is the use of dpp-4 inhibitors safe in patients with sars-cov-2 infection compared to other antidiabetic drugs?
Some reviews and recent guidelines [bib_ref] Sitagliptin treatment at the time of hospitalization was associated with reduced mortality..., Solerte [/bib_ref] indicate that DPP-4 inhibitors are very safe, and may even be potentially beneficial for most patients hospitalised with diabetes and COVID-19.
DPP-4 inhibitors have been found to be safe drugs, and also do not require adjustment on days when patients with diabetes and COVID-19 feel ill, in comparison with other ADAs [fig_ref] Table 4: Recommendations with different antidiabetic drugs in patients with suspected COVID-19 [/fig_ref]. 14 Although only a randomised trial can definitively answer this question, based on molecular, pathophysiological and retrospective studies, the use of DPP-4 inhibitors is safe and certainly beneficial for metabolic control.
Expert consensus: These data support the safety of DPP-4 inhibitors for diabetes control during the COVID-19 pandemic. DPP-4 inhibitors are a group of drugs that offer many advantages, including in severe cases of COVID-19, because they are well-tolerated, entail a low risk of hypoglycaemia and can be used, with dose adjustment if appropriate, in patients with decreased kidney function. In this sense, the use of DPP-4 inhibitors can be considered, including in patients hospitalised with diabetes and COVID-19.

## Given the anti-inflammatory effects of dpp-4 inhibitors, is there any subgroup of patients in whom dpp-4 inhibitors might have an impact on the complications associated with covid-19?
In patients with COVID-19, the hypothesis has been suggested that due to their anti-inflammatory effect, they might help to prevent complications associated with COVID-19. [bib_ref] DPP4 and ACE2 in diabetes and COVID-19: therapeutic targets for cardiovascular complications?, Valencia [/bib_ref] Studies such as the SIDIACO Sitagliptin study

## Are there differences between dpp-4 inhibitors and other pharmacological groups for the treatment of diabetes in patients hospitalised with covid-19?
DPP-4 inhibitors have been found to be safe drugs and do not require adjustment on days of illness in patients with diabetes and COVID-19, in comparison with other oral ADAs 16 ; their use in comparison with other oral ADAs has been associated with shorter ICU stay (level of evidence 2b) and possible benefits in hospitalised patients.

## Expert consensus:
Based on the studies published to date, DPP-4 inhibitors could be considered to have a suitable profile for the treatment of diabetes in hospitalised patients.

# Conclusions
DPP-4 inhibitors are a group of drugs associated with many advantages in the context of the COVID-19 pandemic, including in severe cases, because they are well-tolerated, have a low risk of hypoglycaemia, do not require a dose adjustment on days of illness and can be used in patients with decreased kidney function. After evaluating all the available literature, there is no evidence of sufficient quality to conclusively recommend treatment with DPP-4 inhibitors in patients with diabetes and COVID-19. However, there is also insufficient evidence to advise against their use.
The literature reviewed suggests that there might potentially be substantial benefits to treatment with DPP-4 inhibitors, and we are hopeful that this question will shortly be answered by the high-quality prospective, randomised clinical trials that are currently ongoing.

## Authorship
All the authors contributed equally to the preparation of the article.

# Funding
Medical writing assistance was funded by the Menarini Group. However, none of its members attended the meetings held to review the literature and agree on decisions, nor did they influence the decisions made by the experts.

## Conflicts of interest
Francisco Javier Carrasco-Sanchez: consultant and/or adviser for Boehringer-Lilly, Novo Nordisk, Sanofi,
[fig] Figure 1: PRISMA flow diagram of the article search and selection process. was carried out. The clinical questions of interest were established based on this review. [/fig]
[table] Table 1: Search strategy approach (MeSH descriptors).Targeted search: Cross search of the MeSH term (Dipeptidyl-Peptidase IV Inhibitors) and the MeSH terms (COVID-19) and (Sars-CoV-2) Search extension with the MeSH terms (Dipeptidyl-Peptidase IV Inhibitors) and (DPP4) in free text with the MeSH terms (COVID) and (Sars CoV 2)Extended search: this second search obtained more articles, but with less specificity [/table]
[table] Table 2: COVID-19 disease outcomes by presence of diabetes. [/table]
[table] Table 3: Outcomes of studies with DPP-4 inhibitors in patients with COVID-19. [/table]