Coronavirus disease 2019 (COVID-19) is associated with a high risk of mortality and complications in patients with diabetes mellitus. Achieving good glycemic control is very important in diabetic patients to reduce complications and mortality due to COVID-19. Recent studies have shown the mortality benefit and anti-inflammatory effects of Dipeptidyl-peptidase-4 inhibitors (DPP-4i) in diabetic patients with COVID-19. DPP-4i may have a beneficial role in halting the severity of infection primarily by three routes, namely viral entry inhibition, anti-inflammatory and anti-fibrotic effects and glycemic control. This has raised the pro-mising hypothesis that DPP-4i might be an optimal strategy for treating COVID-19 in patients with diabetes. This review aims to summarise the possible therapeutic non-glycemic effects of DPP-4i in diabetic patients diagnosed with COVID-19 in the light of available evidence.

The current coronavirus disease 2019 (COVID-19) pandemic is caused by a novel beta coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is similar to SARS-CoV-1 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV)[1]. Since late 2019, the disease has spread rapidly worldwide, posing a significant threat to public health. To date more than 539 million patients have been infected across the globe leading to over 6.32 million deaths[2]. The overall mortality rate for COVID-19 ranges from 0.7% to 10.8%[3]. Nearly two-thirds of severely affected individuals have comorbidities, most commonly cardiometabolic disorders, with diabetes mellitus (DM) accounting for 17% of cases[4].

Although DM is not associated with an increased risk of COVID-19, it confers a high risk of rapid progression in the severity of the infection and hence a poor prognosis. Specifically, people with DM are more prone to invasive mechanical ventilation, intensive care unit (ICU) admission, and the development of organ dysfunction, as compared with patients without diabetes[5,6]. A recent meta-analysis of 83 eligible studies with 78874 COVID-19 hospitalized patients found that people with pre-existing DM had a doubling of the risk for severe or critical COVID-19 illness (odds ratio [OR] 2.10, 95% confidence interval [95%CI] 1.71-2.57) and a tripling of the risk for in-hospital mortality (OR 2.68, 95%CI 2.09-3.44)[7]. Putative pathogenic processes linking COVID-19 and DM include hyperglycemia-mediated immune dysregulation, inflammation, and activation of the renin-angiotensin-aldosterone pathway[8].

The increasing spread of the SAR-CoV-2 infection and the high morbidity necessitates rapid identification of an effective therapy. While developing novel therapies (such as antivirals and vaccines) is a priority, repurposing "old" medications or reconsidering previously well-characterized targets with an emerging function in COVID-19 is the need of the hour. Dipeptidyl-peptidase-4 (DPP-4), also known as cluster of differentiation 26 (CD26), has recently been suggested as a potential target receptor for SAR-CoV-2[8,9]. MERS-CoV, a beta coronavirus similar to SARS-CoV-2, uses DPP-4 as an entrance receptor. Due to its similarity with the MERS-CoV, it has also been proposed that DPP-4 may aid SARS-CoV-2 entry into the target cells[10]. In this context, DPP-4i have gained increasing interest as a therapeutic target in patients with COVID-19.

DPP-4 is a 110 kDa glycoprotein, a membrane-bound endopeptidase that cleaves many peptide hormones such as cytokines, growth factors, and incretin hormones like glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP)[11]. Also, DPP-4 interacts with cellular proteins such as adenosine deaminase and caveolin-1 to regulate immune responses[12]. DPP-4 exists in two forms in the body, a membrane-bound form or as a soluble form (sDPP-4)[13]. The extracellular portion of DPP-4 is cleaved from cell membranes to form the 727 amino acid soluble moiety sDPP-4, which circulates in the plasma with retained enzyme activity. The DPP-4 receptor is found on the surface of nearly every cell and plays a role in immune regulation, signaling, and cell apoptosis. It is widely expressed in many tissues such as the kidney, gastrointestinal tract, and lungs. The primary role of DPP-4 is to regulate glucose and insulin metabolism by degradation of incretin hormones such as GLP-1 and GIP. Visceral adipose tissue has greater expression of DPP-4 and it has been linked to adipocyte inflammation and insulin resistance. DPP-4 promotes inflammation in subjects with type 2 diabetes through both catalytic and noncatalytic pathways. DPP-4 directly regulates the immune system by activating T cells and upregulating CD86 expression and the nuclear factor kappa B (NF-kB) pathway[14].

DPP-4i are oral anti-diabetic drugs that affect glucose homeostasis by inhibiting the enzyme DPP-4. DPP-4i prolong the half-life of incretins by deactivating DPP-4, which cleaves and inactivates them. Incretin hormones, GLP-1 and GIP are responsible for the regulation of postprandial insulin[15]. DPP-4i have been suggested to have cardiovascular benefits. Hence, these medications are commonly used in diabetic patients with a history of cardiovascular or chronic renal disease[16]. They achieve reasonable glycemic control with no significant effect on body weight, no risk of hypoglycemic events, and a safe cardiovascular profile. They have also shown a favorable effect on surrogate vascular markers, such as lipid profile, blood pressure, and endothelial function[13].

DPP-4i can effectively control blood glucose levels with a favorable safety profile. Good glycemic control can improve the prognosis and outcome of COVID-19[17]. Hence, DPP-4i can influence the clinical outcome in COVID-19 patients through their glycemic effects. The mechanisms by which DPP-4i influence the clinical outcomes in COVID-19 patients with DM beyond their glycemic effect are still under speculation and are detailed below (Figures 1 and 2).

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Figure 1 Proposed mechanisms of dipeptidyl peptidase-4 inhibitors in coronavirus disease 2019 infection. ACE2R: Angiotensin converting enzyme 2 receptor; COVID-19: Coronavirus disease 2019; DPP-4: Dipeptidyl peptidase-4; FOXP3: Forkhead box P3; IL: Interleukin; mDPP4: Membrane bound DPP4; sDPP4: Soluble DPP4; TGF-β: Transforming growth factor beta.

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Figure 2 Hypothetical interactions between dipeptidyl peptidase-4 and severe acute respiratory syndrome coronavirus 2 virus. ACE-2: Angiotensin-converting enzyme 2; ACE2R: Angiotensin converting enzyme 2 receptor; DPP-4: Dipeptidyl peptidase-4; mDPP4: Membrane bound DPP4; sDPP4: Soluble DPP4.

With the above hypothesis, several observational studies have been performed to investigate the impact of DPP-4i on clinical outcomes in type 2 diabetes mellitus (T2DM) patients hospitalized for COVID-19 (Table 1).

In a cohort study conducted at the university hospital of Padova, amongst 403 patients hospitalized for COVID-19, 85 had DM, and nine were on DPP-4i. DPP-4i users and comparators had no significant difference in ICU admission or death rate[38]. In a retrospective observational study of 120 patients with diabetes, Chen et al[39] found that DPP-4i users and non-users had identical clinical outcomes. Users of DPP-4i had a non-significant higher rate of in-hospital death than non-users (OR 1.48, 95%CI 0.4-5.53). Similarly, after propensity score matching, Pérez-Belmonte et al[40] found that DPP-4i users were not at higher risk for adverse outcomes such as ICU admission, mechanical ventilation, multi-organ dys-function, or long-term hospital admissions. In a few other observational studies there was no link between DPP-4i therapy and COVID-19-related mortality[41-46] and severity[44,47].

On the contrary, few observational studies have revealed that DPP-4i have favourable effects on COVID-19-related outcomes. In a case series encompassing 387 patients admitted to a research hospital in Lombardy (Northern Italy) with COVID-19, 90 patients were diabetic and 12.2% were on DPP-4i. After adjusting for confounders, DPP-4i use was associated with a decreased death risk [adjusted hazard ratio (HR) 0.13; 95%CI 0.02–0.92]. Furthermore, DPP-4i users required less non-invasive mechanical ventilation, implying that their pneumonia was less severe[48].

In a multicentric retrospective observational study conducted in Northern Italy, 169 age and gender-matched subjects treated with sitagliptin plus insulin were compared with a similar number of subjects treated with insulin therapy. Primary outcomes assessed were hospital discharge and death, and secondary outcomes analyzed were ICU admission, the need for mechanical ventilation, and extracorporeal membrane oxygenation. The sitagliptin users had significantly lower mortality (18% vs 37%, P < 0.001) even after adjusting for confounders like age, gender, comorbidities, and ongoing treatment (HR 0.44; 95%CI 0.29-0.66). On day 30, a larger number of patients treated with sitagliptin were discharged from the hospital than those on conventional therapy (71% vs 59%, P < 0.01). Compared to usual treatment, sitagliptin was associated with a lower probability of needing mechanical ventilation and ICU admission. At follow-up, patients treated with sitagliptin had significantly lower inflammatory markers such as procalcitonin and CRP and lower mean blood glucose levels during hospitalization[49].

Similarly, a Korean database-based retrospective study found that DPP-4i treatment was significantly associated with better clinical outcomes even after adjusting for age, gender, comorbidities, and medications (adjusted OR 0.362, 95%CI 0.135-0.971). The study included 832 subjects with DM, of whom 263 were on DPP-4i[50]. Similarly, DPP-4i usage was related to a shorter ICU stay in 67 patients with DM admitted with COVID-19 pneumonia in a single centre in Iraq (OR 0.3, 95%CI 0.2-3)[51].

In the coronavirus disease and diabetes outcome (CORONADO) study, a multicentric prospective observational trial conducted in France, 2796 patients hospitalized for SARS-CoV-2 with DM were assessed. Around 21.6% of the participants were on DPP-4i. The primary outcome as assessed by the need for mechanical ventilation and/or death within seven days was similar in DPP-4i users compared to nonusers (OR 0.83; 95%CI 0.67-1.03)[52]. Wong et al[53] retrospectively analyzed 1214 T2DM patients with confirmed COVID-19 admitted to public hospitals in Hong Kong. They found a lower risk for clinical deterioration (OR = 0.71, 95%CI 0.54-0.93), hyperinflammatory syndrome (OR = 0.56, 95%CI 0.45-0.69) and invasive mechanical ventilation (OR = 0.30, 95%CI 0.21-0.42) in DPP-4i users. However, DPP-4i users had no significant in-hospital mortality reduction.

A retrospective review of 717 COVID-19 patients admitted to a health care centre in Singapore found contradictory results. Patients on DPP-4i (n = 27) showed greater odds of ICU admission than those on other glucose-lowering medicines (adjusted relative risk [RR] 5.14, 95%CI 1.5-17.7). Also, patients on DPP-4i were more likely to require mechanical ventilation; however, no data on mortality were provided[54]. Similarly, Khunti et al[55] in their nationwide observational cohort study in the UK analysed the HR of COVID-19-related mortality in people prescribed DPP-4i. DPP-4i users had a HR of 1.07 (95%CI 1.01-1.13) for COVID-19-related mortality.

The evidence available from observational studies on the link between DPP-4i and DM and COVID-19 outcomes suggests some heterogeneity. These outcomes were extensively evaluated in multiple meta-analyses[56-62]. Bonora et al[56] analyzed seven studies that reported data on mortality. There was no significant difference in death rate between patients treated with DPP-4i and other anti-diabetic medications (RR 0.74, 95%CI 0.47–1.16). Han et al[57] also showed similar results with a statistically non-significant lower mortality (OR 0.95, 95%CI 0.72-1.26) or poor composite outcomes (OR 1.27, 95%CI 0.91–1.77) in diabetic COVID-19 patients. Similarly, Pal et al[58] included nine observational studies of high quality consisting of 7008 COVID-19 patients with DM. A pooled analysis of unadjusted and adjusted data revealed no significant link between DPP-4i usage and mortality. However, subgroup analysis discovered that DPP-4i use in the hospital (rather than before admission) was related to lower mortality (adjusted OR 0.27, 95%CI 0.13-0.55). Contrary to the above studies, Nguyen et al[59] in their recent meta-analysis linked DPP-4i to a higher mortality risk (OR 1.23, 95%CI 1.07-1.42).

DPP-4i appear to have a neutral action in COVID-19, but the available studies are still insufficient to draw definitive conclusions. It is worth noting that all the data are from retrospective observational studies and that most of them were not specifically designed to study the effects of DPP-4i. The discrepancies reported for the connection between DPP-4i and COVID-19 outcomes could be explained by variations in methodology, baseline characteristics, and sample size.

Two randomized controlled trials (RCTs) have evaluated DPP-4i in patients with diabetes and COVID-19 (Table 2).

Abuhasira et al[63] investigated 64 patients who were randomized to receive linagliptin 5 mg once daily or standard of care medication in an open-label, prospective, multicentre RCT (32 in each group). The time to clinical improvement within 28 d of randomization was the primary outcome measured. Treatment with linagliptin in addition to standard therapy did not enhance time to resolution of symptoms (HR 1.22, 95%CI, 0.70-2.15) or death on day 28 (OR 0.56, 95%CI 0.16-1.93). Furthermore, no differences in any of the secondary outcomes, such as the proportion of patients admitted to an ICU, mechanical ventilation rates, length of hospitalization, or supplemental oxygen use, were observed between the study groups. However, due to containment of the COVID-19 epidemic in Israel, the experiment was prematurely terminated, leaving the study underpowered to identify possible differences in the primary results and mortality.

In a parallel, double-blind RCT, Guardado-Mendoza et al[64] evaluated the efficacy of the combination of linagliptin and insulin on metabolic control and prognosis in hospitalized patients with COVID-19 and DM. A total of 73 patients were randomly assigned to either 5 mg linagliptin plus insulin (LI group, n = 35) or insulin alone (I group, n = 38). The need for assisted mechanical ventilation and mortality were the two primary outcomes. Secondary outcomes were glucose levels and insulin requirements during the first 5-10 days in the hospital, pulmonary parameters, and clinical progression of COVID-19. Both groups had similar average hospital stays (12 ± 1 vs 10 ± 1 d, P = 0.343). Three patients in the LI group and twelve in the I group needed assisted mechanical ventilation (HR 0.258, 95%CI 0.092-0.719), and two patients in the LI group and six in the I group died after a 30-d follow-up period (P = 0.139). The inclusion of linagliptin reduced the relative risk of assisted mechanical ventilation by 74% and improved pre- and postprandial glucose levels, requiring less insulin and posing no increased risk of hypoglycemia.

Beyond their well-known glycemic role, DPP-4i have anti-inflammatory, immunomodulatory, and anti-fibrotic properties. They are among the non-insulin glucose-lowering medications that are safe and effective in treating T2DM, even in the presence of COVID-19, without increasing the risk of significant side effects such as hypoglycemia. As a result, practical recommendations for the management of diabetes in patients with COVID-19 do not propose stopping DPP-4i. Even though results from observational studies and a few RCTs have been inconsistent, the existing evidence suggests that DPP-4i are safe for patients with T2DM and COVID-19. Studies showed a trend towards reducing mortality in COVID-19 patients with DM, especially with continued in-hospital use of DPP-4i. As a result, it is appropriate to start or continue DPP-4i in COVID-19 individuals with DM unless contraindicated.