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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 131-136

Dipeptidyl-peptidase-4 inhibitors in type 2 diabetes and COVID-19: From a potential repurposed agent to a useful treatment option


1 Department of Diabetes & Endocrinology, G.D Hospital and Diabetes Institute, Kolkata, India
2 Department of Gynecology & Obstetrics, G.D Hospital and Diabetes Institute, Kolkata, India

Date of Submission25-Jun-2020
Date of Decision30-Jun-2020
Date of Acceptance06-Jul-2020
Date of Web Publication1-Sep-2020

Correspondence Address:
Dr. Awadhesh Kumar Singh
Department of Diabetes & Endocrinology, GD Hospital and Diabetes Institute, Kolkata, West Bengal.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JOD.JOD_53_20

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  Abstract 

Dipeptidyl-peptidase-4 inhibitors (DPP-4Is) are very commonly prescribed antidiabetic agents in the treatment of type 2 diabetes owing to its modest ability to reduce blood glucose without ensuing any hypoglycemia and weight gain. Many experts have advised continuing DPP-4Is in patient with type 2 diabetes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19). In addition, several researchers have proposed DPP-4Is to be used as a repurposed agent for COVID-19 not only for the patients with diabetes but also for those without diabetes. We aimed to review as to what could be the reason behind this approach and how does the use of DPP-4Is alter the outcome in patients with type 2 diabetes and COVID-19.

Keywords: Coronavirus disease 2019, dipeptidyl-peptidase-4 inhibitors, outcomes, severe acute respiratory syndrome coronavirus 2, type 2 diabetes


How to cite this article:
Singh AK, Singh R. Dipeptidyl-peptidase-4 inhibitors in type 2 diabetes and COVID-19: From a potential repurposed agent to a useful treatment option. J Diabetol 2020;11:131-6

How to cite this URL:
Singh AK, Singh R. Dipeptidyl-peptidase-4 inhibitors in type 2 diabetes and COVID-19: From a potential repurposed agent to a useful treatment option. J Diabetol [serial online] 2020 [cited 2020 Nov 26];11:131-6. Available from: https://www.journalofdiabetology.org/text.asp?2020/11/3/131/294049




  Introduction Top


Both angiotensin-converting enzyme-2 (ACE2) and dipeptidyl-peptidase-4 (DPP-4), respectively, have been found to be the principal entry receptor for the past coronavirus (CoV) infections such as severe acute respiratory syndrome (SARS-CoV-1) and Middle East Respiratory Syndrome (MERS-CoV). Certain polymorphisms of DPP-4 have been associated with a reduced risk of MERS-CoV infection in an experimental study. It was also speculated that the presence of protective polymorphisms of DPP-4 in Africans may explain the perplexing absence of MERS-CoV cases in Africa.[1] Although the ACE2 is also the principal entry receptor for the current pandemic of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2, a recent modeling study by Vankadari and Wilce[2] did not rule out the interaction of SARS-CoV-2 with the DPP-4. A crystallographic study by Li et al.,[3] using a bioinformatics approach, reported that both ACE2 and DPP-4 could be among the top five proteins that may be involved with the receptor-binding domain (RBD) of SARS-CoV-2, beside others such as DPP-6, DPP-10, and fibroblast activation protein (FAP). In addition, it was also proposed that among the three coronaviruses, only SARS-CoV-2 can theoretically bind to both ACE2 and DPP-4. Other hypothesis that has been proposed relates to an inherent nature of a high mutation rate with all RNA viruses, including the previous coronavirus such as SARS-CoV-1 and MERS-CoV. SARS-CoV-2 could also possibly possess an easy mutational characteristic. It is believed that SARS-CoV-2 may continually mutate to adapt to the changes in the environment by invading cells via coupling with DPP-4. These developments suggest that although SARS-CoV-2 may not directly involve DPP-4 as an entry receptor, however their interaction with DPP-4 in conjunction with ACE2 and likely mutation leading to an involvement of DPP-4 directly cannot be entirely ruled out at the moment. Owing to these developments, DPP-4 inhibitors (DPP-4Is) has recently gained importance and has been thought to possess some potential against the SARS-CoV-2.[4]

DPP-4 inhibitors as a repurposed agent in type 2 diabetes and COVID-19

The scientific basis for proposing DPP-4Is as a potential repurposed agent in the treatment of patients with COVID-19 and (or even without) diabetes is as follows:

A seminal work by Zhang et al.[5] recently identified a main protease named Mpro or 3CLpro from the crystal structure of SARS-CoV-2 viral protease. Mpro is a cysteine protease, and Mpro dimer is the catalytic active form with its catalytic amino acid His41 and Cys145. As membrane-bound DPP-4 is active as a dimer having three active catalytic amino acids—His740, Ser630, and Asp708, Rao et al.[6] in a pharmacophore modeling and a molecular docking studies showed that peptidomimetic class of DPP-4Is exhibit an excellent binding to the SARS-CoV-2 viral protease. Of the 12 total DPP-4Is studied by Rao et al.[6] (including sitagliptin, vildagliptin, linagliptin, saxagliptin, alogliptin, gemigliptin, trelagliptin, omarigliptin, evogliptin, teneligliptin, anagliptin, and gosogliptin), based on their chemical structure, three DPP-4Is have been shown to possess the best CDOCKER energies as well as CDOCKER interaction energies in binding to the SARS-CoV-2 viral protease. These three DPP-4Is in order of ranking include gemigliptin > linagliptin > evogliptin. Interestingly, non-peptidomimetic DPP-4Is (such as omarigliptin) and dipeptide-nitrile containing covalent DPP-4Is (such as vildagliptin and saxagliptin) were found to show the least effect. All other remaining DPP-4Is, fall in between these two spectra. It should be recalled that linagliptin, sitagliptin, and alogliptin are substrate competitive inhibitors, whereas saxagliptin and vildagliptin act as a pseudosubstrate. Nonetheless, the big learning gap that is still unknown is whether DPP-4I-induced conformational changes have the ability to modify the SARS-CoV-2-linked DPP-4 interaction.

Interestingly, past in vitro studies conducted by Raj et al.[7] found that antibodies directed against the DPP-4 significantly inhibit the human coronavirus-Erasmus Medical Center (hCoV-EMC) infection of Huh-7 cells as well as the primary human bronchial epithelial cells. Intriguingly, the application of three DPP-4Is such as sitagliptin, vildagliptin, and saxagliptin was not able to inhibit the hCoV-EMC infections. This finding apparently hints that even after the binding with DPP-4Is, the bound DPP-4 receptor-binding domain is unable to alter the substrate that accesses the catalytic sites. In contrast, a humanized anti-CD-26 monoclonal antibody (YS110), that targets the site between the binding domain on the virus surface and the receptor that alters DPP-4 level, significantly suppressed MERS-CoV infection.[8] Collectively, it is yet unclear whether DPP-4Is would be able to alter the course even if SARS-CoV-2 uses DPP-4 as an entry receptor.

In a recent study, Hoffmann et al.[9] has shown that camostat mesylate, a serine protease inhibitor efficiently suppresses the SARS-CoV-2 infection by inhibiting the transmembrane serine protease 2 (TMPRSS2) that cleaves the Spike (S) protein, which helps in the membrane fusion and internalization of SARS-CoV-2. This finding also led to believe that DPP-4Is by virtue of inhibiting another serine protease DPP-4, could be useful as a repurposed agent if it is involved along with the ACE2 by the SARS-CoV-2.

Other reasons that make DPP-4Is a repurposed candidate in COVID-19 is its anti-inflammatory, anti-fibrotic, and immunomodulator properties. Both experimental and human studies have shown DPP-4Is to exert a potent anti-inflammatory effect, by reducing pro-inflammatory cytokines. Intuitively, this may appear to help in curbing inflammatory storm in patients with COVID-19. In a diabetic mouse model, saxagliptin reduced the activation of the NOD-like receptor 3 (NLRP3) inflammasome and reduced the serum levels of C-reactive protein (CRP), tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β, and IL-18.[10] In other mouse model study, both vildagliptin and saxagliptin have shown a significant anti-inflammatory effect that was comparable to that of aspirin.[11] In a human study, a significant reduction in CRP, IL-6, and messenger ribonucleic acid (mRNA) expression of CD26 in mononuclear cells (16%) within 2h after a single dose of sitagliptin was observed.[12] With regard to the anti-fibrotic properties of DPP-4Is, a study in animal model found sitagliptin to be highly effective in alleviating the histological findings of lung injury by virtue of reducing inflammatory cytokines.[13] In addition, sitagliptin was found to reduce bleomycin-induced lung and skin fibrosis in preclinical systemic sclerosis mouse models.[14]In vitro study also found that sitagliptin inhibited lung fibroblasts activation induced by TGF-β.[15] The immunomodulatory effect of DPP-4Is has been witnessed in improving several autoimmune diseases (ADs). Experimental studies have found DPP-4Is to decrease the incidence, symptoms, and disease severity in autoimmune encephalomyelitis due to multiple sclerosis.[16] Human study also found DPP-4/CD-26 inhibitors suppressing the activation of myelin basic protein-specific CD4+ T cell clones.[17] Real-world studies from the two large databases also suggest DPP-4I users had significantly less AD including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus, and multiple sclerosis, compared to the nonusers. In a real-world study from the Korean national health insurance database (n = 1,140,784), the risk of incident AD was significantly lower (adjusted hazard ratio [HR], 0.76, 95% confidence interval [CI], 0.62–0.93) in DPP-4I users compared to that in the nonusers in a propensity-matched analysis after a follow-up of 1 year.[18] Another population-based study (n = 236,990) from the US insurance claim database with a follow-up of more than 1 year, also found a significant 34% decrease in RA (HR, 0.66; 95% CI, 0.44–0.99) among DPP-4I users compared to that among the nonusers; although, no difference was observed in propensity-matched analysis.[19]

Counterintuitively, DPP-4 inhibition can affect immunity offered by the effector T cells by altering its activity, and therefore, theoretically DPP-4Is can suppress immunity. An increased association of DPP-4Is with bullous pemphigoid and IBD has been implicated to its T cell–mediated effects.[20],[21] Furthermore, as lymphocyte protein CD-26 is structurally similar to DPP-4, there is some apprehension that inhibition of CD-26/DPP-4 by the DPP-4Is can be associated with an increased risk of infections. Indeed, the initial reports of increase in nasopharyngitis with the DPP-4Is were documented during the Phase 3 clinical development program, although the later meta-analysis as well as the long cardiovascular outcome trials did not find any such signals. Moreover, two studies conducted with sitagliptin in immunocompromised individuals, with human immunodeficiency virus (HIV) with or without dysglycemia, found no significant increase in infections.[22],[23] Another concern observed was the interstitial pneumonitis implicated to vildagliptin in some case series, which was also alerted by the Japanese Adverse Events Reports.[24],[25],[26] However, a large study from the UK-based Clinical Practice Research Datalink (CPRD) database that studied 103,159 patients of diabetes over a follow-up of 8 years and compared the rate of respiratory tract infection with DPP-4Is to the sulfonylureas, metformin, thiazolidinediones, and insulin, found no significant increase in risk.[27]

Finally, emerging data also suggest an increased association of COVID-19 to the elderly population, and people with diabetes and obesity, all of whom often exhibit a heightened DPP-4 activity, and therefore it is believed that DPP-4Is could be tried as a repurposed agent in patients with diabetes who are elderly and/or obese, which often coexists.

Collectively, based on these findings, a sense of optimism with DPP-4I has been expressed by many researchers and clinicians.[28],[29],[30],[31] As a matter of fact, several experts group had opined to continue DPP-4Is in patients with diabetes and COVID-19, owing to its safety record, despite the absence of any clinical trials available at that point of time.[32],[33] Nevertheless, some expert feels these effects of DPP-4Is to be equivocal,[34] whereas some suggest to maintain a caution.[35]

Studies with DPP-4Is in patients with type 2 diabetes and COVID-19

Very limited number of studies is currently available that has reported the outcomes in DPP-4I users in patients with diabetes and COVID-19. In a propensity-matched analysis (n = 500), Zhu et al.[36] reported a significant decrease in all-cause mortality in patients with well-controlled blood glucose compared to that in patients with poorly controlled diabetes (adjusted HR, 0.14; 95% CI, 0.03–0.60; P = 0.008). Interestingly, a significantly higher proportion of patients were receiving DPP-4Is in the well-controlled arm as compared to the poorly controlled cohorts (11.2% vs. 4.4%, P = 0.008). Although this finding does not necessarily support the direct benefit of DPP-4Is and has been implicated mainly to the good glycemic control, however this at least hints of no harm. Moreover, only 39 patients were receiving DPP-4Is in this study.

Chen et al.[37] studied the record of 120 patients receiving different oral antidiabetic agents, of which 20 patients were receiving DPP-4Is. The rate of in-hospital death and poor prognosis in DPP-4I users versus nonusers was found to be similar (in-hospital death: 25% vs. 14%, respectively, P = 0.31; poor prognosis: 75% vs. 65%, respectively, P = 0.45). The multivariate logistic regression analysis also found no significant difference in in-hospital death (odds ratio [OR], 1.48; 95% CI, 0.40–5.53; P = 0.56) and poor prognosis (OR, 1.81; 95% CI, 0.51–6.37; P = 0.36) between DPP-4I users versus the nonusers. Thus, this study found no benefit or harm with DPP-4Is.

In CORONADO (coronavirus disease and diabetes outcome), an observational prospective trial (n = 1317) conducted in patients with diabetes and COVID-19, 285 patients were receiving DPP-4Is. The primary outcome of tracheal intubation and/or death evaluated within 7 days of admission in DPP-4I users had a similar outcome compared to that in the nonusers (unadjusted OR, 1.01; 95% CI, 0.75–1.34; P = not reported [NR]). The secondary outcome (death at day 7) was also similar in DPP-4I users compared to that in the nonusers (unadjusted OR, 0.85; 95% CI, 0.55–1.32; P = NR). This study hinted of no benefit or harm with DPP-4Is in patients with diabetes and COVID-19.[38]

In a retrospective study, Fadini et al.[39] analyzed the 85 patients with diabetes and COVID-19, of which 9 were receiving DPP-4Is. In an unadjusted analysis, there was no significant difference in the rate of intensive care unit (ICU) admission (33.3% vs. 19.2%, respectively, P = 0.33) or death (11.1% vs. 13.9%, respectively, P = 0.82) between DPP-4I users (10.6%) compared to the nonusers. Moreover, when it was compared to the well-matched controls (patients with diabetes receiving DPP-4Is but not having COVID-19), no significant increase in hospitalization for pneumonia either due to COVID-19 or of other etiology was observed among the DPP-4I users (OR, 1.11; P = 0.97). This finding suggests no benefit or harm with DPP-4Is in patients with diabetes and COVID-19.

In a French case series of 27 patients with diabetes, of which 10 were receiving DPP-4Is, Montastruc et al.[40] reported a lower rate of intubation in DPP-4I users compared to that in the nonusers (43% vs. 81%, respectively; P = NR). This is the first small study that hinted of benefit with DPP-4Is in patients with diabetes and COVID-19.

A study by Rhee et al.[41] from the South Korean Medical insurance claim database reported the population-based study of 832 patients with diabetes and COVID-19, of which 263 were taking DPP-4I. This study showed a significantly (64%) less severe COVID-19 in DPP-4I users compared to that in the nonusers (adjusted OR, 0.36; 95% CI, 0.14–0.97; P = NR), even after the adjustment of age, sex, comorbidities, and medications. Further stratification based on either DPP-4I only users (n = 133) or DPP-4I plus renin-angiotensin blocker (RASB) users (n = 130), respectively, also found a significantly less severe COVID-19 in DPP-4I users compared to that in the nonusers (DPP-4Is only: adjusted OR, 0.23; 95% CI, 0.06–0.95 and DPP-4Is plus RASB: adjusted OR, 0.25; 95% CI, 0.07–0.85; both P = NR, respectively). This finding clearly suggests a significantly less severe COVID-19 in patients with diabetes in DPP-4I users irrespective of additional RASB usage, compared to the DPP-4I nonusers. [Table 1] summarizes the results from all the available clinical studies.
Table 1: Outcomes with DPP-4 inhibitors in studies conducted on patients with type 2 diabetes and COVID-19

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A case–control study with eponym SIDIACO (sitagliptin in diabetic patients with COVID-19) is currently evaluating the clinical response with 10 days course of 100mg sitagliptin, in patients with diabetes and COVID-19, at Sacco Hospital and San Matteo Hospital in Milan and Pavia, respectively, in Italy.[42]

Future randomized controlled trials of DPP-4Is in patients with type 2 diabetes and COVID-19

To date, two randomized controlled trials (RCTs) are currently evaluating the DPP-4Is in patients with diabetes and COVID-19. Both studies are examining the effect of linagliptin 5mg daily in a background of insulin therapy compared to the control on insulin. One study is undergoing in Israel (NCT04371978) and evaluating 100 patients with diabetes and established COVID-19, with a primary objective of time to clinical change within 28 days. The clinical change is defined as two-point reduction in the World Health Organization’s eight-point ordinal scale for clinical improvement of COVID-19.[43] This study is expected to be completed in June 2021.

Another study is being carried out in USA (NCT04341935) and evaluating 20 patients with diabetes, and confirmed COVID-19 using linagliptin 5mg daily in a background of insulin therapy and being compared to the control on insulin alone. Although the primary outcome of this 14-day study is changes in glucose control, the secondary outcome includes changes in oxygen saturation (SpO2 levels), changes in IL-6 and changes in chest radiography.[44] This study is expected to be completed in October 2020.


  Conclusion Top


Collectively, available data clearly suggest that DPP-4Is produce no harm in patients with diabetes and COVID-19. Moreover, there is an emerging evidence that it can be perhaps useful in lowering the risk of severe COVID-19, as observed in at least one relatively large retrospective study. Nonetheless, this is miniscule evidence at the moment to confidently conclude that DPP-4Is could substantially modify the outcome in patients with diabetes and COVID-19. Future RCTs will help us in understanding the role of DPP-4Is in patients with diabetes and COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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