Compiled by Admin on the basis of recently published articles by Dr Awadhesh Kumar Singh, DM, Endocrinology & Dr Ritu Singh, Kolkata.
In a very recent paper published in Journal of Diabetology, eminent endocrinologist, Dr Awadhesh Kumar Singh (Department of Diabetes & Endocrinology, GD Hospital and Diabetes Institute, Kolkata 700013, West Bengal, India) has raised a new curtain for a possible new repurposed use of DPP-4 inhibitors in patients with COVID-19 with type 2 diabetes. Notably, in another paper published by the same authors in Diabetes Research and Clinical Practice, Metformin was found to be ahead in race as a repurposed drug and a frontline anti-diabetic drug. Interestingly, while DPP-4 inhibitors shown a significant reduction in the risk of severe COVID-19 in patients with type 2 diabetes, metformin shown a significant reduction in mortality in some of these retrospective studies. This suggest both these class of drugs that are often used in patients with type 2 diabetes may be a useful weapon in patients with COVID-19 too. However, only a large randomized trial can truly answer whether these agents are really beneficial in the context of COVID-19 and type 2 diabetes.
Salient Points from the article by Dr Awadhesh Kumar Singh & Dr Ritu Singh
What is the scientific basis?
- It is well known that 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).
- 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 modelling study by Vankadari and Wilce did not rule out the interaction of SARS-CoV-2 with the DPP-4.
- A crystallographic study by Li et al., 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.
Why DPP-4 inhibitors as a repurposed agent in type 2 diabetes (or even without) and COVID-19?
- Rao et al. in a pharmacophore modelling and a molecular docking studies showed that peptidomimetic class of DPP-4Is exhibit an excellent binding to the SARS-CoV-2 viral protease.
- Which Gliptin? Of the 12 total DPP-4Is studied by Rao et al. (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 pseudo-substrate. Nonetheless, the big learning gap that is still unknown is whether DPP4I-induced conformational changes have the ability to modify the SARS-CoV-2-linked DPP-4 interaction
- 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.
- Hoffmann et al. 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
- 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
- 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. 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. Nevertheless, some expert feels these effects of DPP-4Is to be equivocal, whereas some suggest to maintain a caution.
Studies with DPP-4Is in patients with type 2 diabetes and COVID-19
- Several retrospective studies are currently available which studied the outcomes in DPP-4I users and compared with non-users. While some studies found no harm or any benefit, few studies found a significantly lower risk of having severe COVID-19 in DPP-4I users compared with non-users.
- 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.  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. This study is expected to be completed in October 2020.
Take Home Message 
- Collectively, available data clearly suggest that DPP-4Is produce no harm in patients with diabetes and COVID19.
- 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 COVID19.
- Future RCTs will help us in understanding the role of DPP-4Is in patients with diabetes and COVID-19. 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.
- Most of the expert consensus have suggested avoiding metformin in patients with diabetes and coronavirus disease-19 (COVID-19), due to an anticipated fear of lactic acidosis in the background of multi-organ dysfunction including hepatic and renal impairment
- Interestingly, the historical use of metformin during influenza and malaria outbreak is somehow analogous to the recent use of anti-influenza and anti-malarial drug as a repurposed agent in the treatment of COVID-19, in the absence of any licensed agent
- Anti-inflammatory properties of metformin
- Metformin may have an ability to improve host-directed response by virtue of inducing adenosine monophosphate (AMP) activated protein kinase. The mechanism by which metformin can reduce inflammation and improve both adaptive and innate immune response include, induction of autophagy, formation of M2 macrophages and CD8 memory T-regulatory cells, besides its ability to reduce the expression of genes that encode chemokines and cytokines. In addition, metformin may have a role as an anti-oxidant by altering the activities of catalase and superoxide dismutase. Furthermore, metformin may also reduce inflammation by altering the composition of gut microbiota. Collectively, these anticipated immunomodulatory, anti-oxidative and antiproliferative properties suggest that metformin could be beneficial in combating the cytokine storm induced host directed damage in patients with diabetes and COVID-19
- Role of metformin in pulmonary disease and sepsis
- Metformin has shown its protective role in legionella pneumonia, in the mouse models. Human studies in the past, that studied metformin in sepsis and lung diseases have consistently shown benefit.
- Metformin in patients with diabetes and COVID-19
- Accumulating evidence now points that continuing treatment with metformin in patients of diabetes with COVID-19 is not harmful and could possibly be beneficial. Study by Zhu et al. that looked for the proportion of patients receiving different anti-diabetic agents, found no harm with metformin. In the comparative analysis (1:1 propensity-matched to other comorbidities) of well-controlled group (blood glucose 70–180 mg/dL) that showed a significant reduction in all-cause mortality (adjusted HR 0.13; 95% CI, 0.04–0.44, p < 0.001), compared to the poorly-controlled arm (blood glucose > 180 mg/dL);
- CORONADO study found that an increase in body mass index was the only factor independently associated with a significant increase in the composite of primary outcome. Notably, amongst all the anti-diabetic agents, only metformin users prior to the admission had a lower rate of death, compared to the metformin non-users (OR 0.59; 95% CI, 0.42–0.84), in an unadjusted analysis. A non-statistical trend of lower death was also observed in metformin users, even after the full adjustment (OR 0.80; 95% CI, 0.45–1.43; p = 0.45). This clearly hints of no harm with metformin in patients with diabetes and COVID-19
- Luo P, Qiu L, Liu Y, Liu XL, Zheng JL, Xue HY, et al. Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis.
Take Home on Metformin in type 2 diabetes and COVID-19
- Metformin can be safely used in mild to moderate cases of type 2 diabetes with COVID-19
- It can be beneficial per se in decreasing mortality
Awadhesh Kumar Singh, Ritu Singh. Is metformin ahead in the race as a repurposed host-directed therapy for patients with diabetes and COVID-19?Commentary in diabetes research and clinical practice| volume 165, 108268, July 01, 2020
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. DOI: 10.4103/jod.jod_53_20
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