The findings from this sizeable COVID-19 registry study indicate that preexisting treatment with DPP-4is may be associated with a reduction in mortality in patients with T2DM. The nearly 50% lower mortality observed in this group is also reassuring in terms of their safety during the COVID-19 pandemic. Although the rate of hospitalization was similar between the group on DPP-4is and the group on other glucose-lowering medications, patients on DPP-4is in our study clearly had a lower rate of ICU admission and/or mechanical ventilation.
DPP-4 (or CD26) is a transmembrane glycoprotein expressed ubiquitously in various tissues, including the immune cells, endothelium, liver, kidney, and pneumocytes . Apart from its role in glucose and insulin metabolism, the DPP-4 receptor also interacts with the spike glycoprotein of SARS-CoV-2 virus to facilitate its invasion into respiratory cells . Therefore, the upregulation of the DPP-4 receptor, a common feature of people with chronic diseases, might be another reason for the increased COVID-19 severity in these people . It has been shown that DPP-4 receptor antibodies can prevent coronavirus infection by preventing the entry of viral particles into the human bronchial epithelial cells [17, 18]. The results of these two in vitro studies are exciting as they imply that DPP-4is have the potential to reduce the severity of COVID-19 infection by their anti-viral and anti-inflammatory effects [19, 20].
Although the preclinical data on the benefit of DPP-4 inhibition in COVID-19 prognosis are promising, no evidence from randomized controlled clinical studies is currently available. Thus, at the present time clinical evidence is mainly observational. Two recent retrospective studies performed in different regions of Italy reported that preexisting treatment with DPP-4is in patients with T2DM was associated with improved COVID-19 outcomes, including reduced mortality [21, 22]. One of these studies was a multicenter, case–control study that analyzed 164 patients on sitagliptin; the authors reported a 56% reduction in mortality due to COVID-19 . The other single-center study included 101 patients with T2DM, of whom 11 were receiving DPP-4is; these authors reported an 87% reduction in COVID-19 mortality . However, several other studies of a similar design did not confirm the benefits of DPP-4is on the COVID-19 outcomes [23,24,25,26,27,28,29].
Because of the small number of patients, lack of randomization, and insufficient reporting of secondary outcomes in published studies , several authors have performed meta-analyses. One meta-analysis of six studies (heterogeneity [I2]: 54%) and another of seven studies (I2: 55%) published in December 2020 and January 2021, respectively, revealed no significant difference in the risk for the development of a fatal or severe course of illness with the use of DPP-4is in patients with COVID-19 [31, 32]. Two subsequent meta-analyses with very low heterogeneity, published in February 2021 and March 2021 and included nine and ten studies, respectively, came to similar conclusions [33, 34], with the exception of some benefits of in-hospital use of DPP-4is. More recently, Rakhmat et al. published a meta-analysis of nine studies and reported that taking DPP-4is was associated with lower mortality in COVID-19 patients with diabetes mellitus . Their dataset included a total of 4477 patients with diabetes mellitus, of whom 31% were on DPP-4is; the use of DPP-4is was associated with 24% lower mortality in COVID-19 patients . The present analysis included a dataset of 4550 DPP-4i users and an equal number of non-users with full outcome information starting from the day of the PCR-positive COVID-19 diagnosis, making the study larger than any meta-analysis previously published. Our results confirm the findings of a few previous studies and of one of the six meta-analyses that provided evidence of reduced mortality due to COVID-19 in patients with diabetes mellitus who are receiving DPP-4is alone or in any combination. Propensity score matching and multivariate logistic regression allowed us to rule out the potential confounding effects of age, gender, micro- and macro-vascular complications, anti-hyperglycemic medications, RAS blockers, and statins. Obesity has been linked to increased COVID-19 mortality; however, patients in the group taking DPP-4is in our study showed lower mortality than those in the group taking other glucose-lowering medications despite their median BMI being higher and obesity diagnosis more prevalent. Moreover, the odds of lower mortality in patients taking DPP-4is was not small, nearly 50%, suggesting a clinically meaningful finding.
The association of DPP-4i use and hospitalization due to COVID-19 is less known. The rate of hospitalization did not favor DPP-4is over other anti-hyperglycemics in the present study. This finding is in line with a recent report by Fadini et al. , but none of the studies mentioned above evaluated this outcome. The lack of any modification in the rate of hospitalization in users of DPP-4is despite a clear association with reduced mortality is difficult to explain. One explanation may be that DPP-4is might modify the disease course prominently in more severe cases but only have a minor impact on a less progressive clinical picture. Another potential explanation may be the overall high hospitalization rate in our dataset because many individuals were indeed not selectively hospitalized during the initial months of the pandemic. Since our dataset did not allow discrimination of causes of hospitalization, this outcome needs to be elucidated in future studies.
This study has a number of limitations. As with any retrospective cohort study, it is not possible to draw causal inferences between the preexisting treatment with anti-hyperglycemic agents and the outcomes of COVID-19. One of the main limitations could be that the testing protocol for COVID-19 was not universal and that many of the mild cases would have gone undetected. Therefore, only moderate to severe cases of COVID-19 would have been detected by PCR testing. This may partly explain the finding that while two thirds of the cohort were admitted to hospital there was no difference in the rate of hospitalization between the two groups we studied. Also, since the data were collected from the electronic medical health records of the Turkish Ministry of Health, the absence of some data cannot be ignored. Moreover, the potential effects of unmeasured confounding factors cannot be excluded. It should be noted that no imputation was done during our analyses.
There are also some strengths of the present study, including the largest sample with DPP-4i users so far published, 1:1 matching with control patients with diabetes mellitus, nationwide representation, multicenter design, exclusion of unconfirmed (PCR negative) COVID-19 cases, and the availability of full information on the most relevant COVID-19-related outcomes. Countrywide administration of centrally guided outpatient and inpatient protocols by the Ministry of Health is another strength because standardized protocols may reduce the confounding of the results by the level or the quality of care following COVID-19 diagnosis.