The COVID-19 pandemic has affected older, frail individuals with diabetes particularly severely and there is still no effective treatment for COVID-19 available. Therefore, we performed a multicenter, nationwide, retrospective, observational study to analyze the impact of preadmission cardiometabolic medication on mortality in elderly diabetic patients hospitalized for COVID-19.
Our study suggests that preadmission treatment with DPP-4i and ARB could be associated with reduced in-hospital mortality in elderly patients with T2DM hospitalized for COVID-19 whereas treatment with ASA could be associated with excess mortality. Other antidiabetic drugs, ACEI, and statins showed neutral association with mortality.
So far, there has been no conclusive evidence in regard to the potential implications of cardiometabolic therapies on COVID-19 outcomes, especially among elderly patients. Additionally, whether certain antidiabetic drugs can improve the prognosis of diabetic patients with COVID-19 remains unknown. Studies on glucose-lowering drugs in patients hospitalized with COVID-19 have shown conflicting results. In some reports, the use of oral antidiabetics had a neutral effect on in-hospital mortality and the composite outcome of poor prognosis, defined as progression to severe or critical illness and in-hospital death [19, 20], whereas in other studies, metformin had a beneficial effect on clinical outcomes [16, 18]. Insulin use was associated with a greater risk of poor prognosis compared to not using it [20, 21].
In our study, which was conducted solely in very old patients with T2DM, all antidiabetic therapies showed neutral effects on the clinical outcomes of COVID-19 with the notable exception of DPP-4i which, after exhaustive adjustment for potential confounding factors, were associated with a significant reduction in in-hospital deaths. Overall, data from human studies on the effects of DPP-4i in COVID-19 are scarce. Better clinical outcomes in patients with T2DM and COVID-19 have also been reported in a population-based study of 832 patients from the National Health Review and Assessment Service database in Korea .
In a recent multicenter, case-control, retrospective, observational study of 338 patients with T2DM admitted to hospitals in northern Italy for COVID-19, sitagliptin treatment in conjunction with insulin administration upon admission was determined to be associated with reduced mortality and improved clinical outcomes when compared to standard of care . These potential benefits of DPP-4i in patients with T2DM and COVID-19 must be confirmed in further research and placebo-controlled trials. Currently, there are two ongoing trials analyzing the safety and efficacy of linagliptin in patients with T2DM hospitalized for COVID-19 (NCT04542213, NCT04371978).
Several possible mechanisms have been proposed to explain the potential benefits of DPP-4i in individuals with T2DM and COVID-19 [23–25]. First, T2DM is characterized by an overexpression of DPP-4 receptors, thus their inhibition may have immunoregulatory and anti-inflammatory effects [26, 27]. Second, aging is associated with changes in cellular and humoral immunity that could favor worse outcomes in COVID-19 . Third, DPP-4 has been identified as a receptor for MERS-CoV  and, additionally, the structure of SARS-CoV-2 spike glycoprotein S1, which mediates virus entry into the host cell, has high degree of homology with DPP-4 and angiotensin-converting enzyme 2 (ACE2) . This may indicate that DPP-4 can facilitate SARS-CoV-2 entry into respiratory tract cells [29, 30] and as such, DPP-4 inhibition could contribute to reducing the viral load and improving inflammatory and immune responses so as to prevent a cytokine storm, which can entail lung injury and multiple organ failure in COVID-19 [31, 32].
A previous work from the SEMI-COVID-19 Network that analyzed 2,666 patients with T2DM admitted for COVID-19 did not find any significant associations between at-home glucose-lowering drugs and mortality or other adverse outcomes . However, the mean age of patients in that study was much younger than those in our cohort (75 vs 86 years), a fact that could explain the difference in results. Aging may be associated with DPP-4 overexpression; a significant correlation between membrane DPP-4 activity and animal age has been found in murine models . It has also been reported that DPP-4 receptor levels rise on the senescent cell surface, suggesting that DPP-4 could play an important role in the aging process . Aging is also characterized by a state of chronic low-grade inflammation (termed “inflammaging”) that could predispose patients to experiencing a cytokine storm in COVID-19. Moreover, some preclinical evidence suggests that the anti-inflammatory effects of DPP-4 may be more intense in elderly patients . Taken as a whole, these data could explain why more beneficial effects of DPP-4i are observed in elderly patients with T2DM and COVID-19 than in younger populations.
We found that previous treatment with ARB, but not with ACEI, in elderly patients with T2DM hospitalized for COVID-19 was associated with a lower risk of all-cause mortality, a finding not previously reported in this population. The role of renin-angiotensin-aldosterone system (RAAS) inhibitors in the COVID-19 has not been fully characterized. Given that both ACEI and ARB induce up-regulation of ACE2 , it has been hypothesized that these drugs could augment susceptibility to and severity of SARS-CoV-2 infection . However, data from observational studies indicate that use of RAAS inhibitors in patients with COVID-19 is safe [17, 38]. A large meta-analysis which analyzed 28,872 patients and examined critical events and mortality data on patients prescribed ACEI and ARB found that their chronic use, especially among hypertensive patients with COVID-19, had beneficial effects . In view of the foregoing, continuing ACEI and ARB treatment in COVID-19 patients has been recommended .
In spite of its upregulation of ACE2, the potential benefits of RAAS inhibitor treatment in COVID-19 could be explained through its enhancement of the ACE2/Ang1 − 7/Mas axis. It converts angiotensin II into Ang1 − 7, which has anti-inflammatory properties that preclude lung injury due to COVID-19 [41, 42]. Aging is associated with an upregulation of the angiotensin II proinflammatory pathway as well as a decrease in ACE2 levels and this likely predisposes elderly diabetic individuals to more severe COVID-19 disease .
Since ARB act on the final step of the RAAS system, blocking the AT1 receptor of angiotensin II, it has been postulated that they might be superior to ACEI in terms of improving COVID-19 prognosis . In fact, better outcomes have been described in patients with COVID-19 and hypertension who receive ARB versus ACEI . Until more evidence is available, it would be wise to prioritize the use of ARB over ACEI in this population.
This work also found that preadmission therapy with ASA was associated with increased in-hospital mortality in very old patients with diabetes hospitalized for COVID-19. One retrospective study concluded that ASA use may have protective effects on the lungs and reduce the need for mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized COVID-19 patients . This is likely related to the antithrombotic and anti-inflammatory properties of ASA. However, in that work, the mean age of ASA-treated patients was 62 years and only 55% had diabetes, so these results cannot be extrapolated to older diabetic patients.
The impact of ASA use on all-cause mortality in elderly patients is uncertain, as both favorable  and unfavorable  effects have been reported. In the ASPREE trial , which analyzed healthy patients ≥ 70 years of age, low-dose aspirin significantly increased the risk of major bleeding events and mortality. In light of this finding, the potential benefits of ASA use must be weighed against the risk of hemorrhage and other adverse effects in elderly diabetic individuals, especially those without prior cardiovascular disease .
Finally, preadmission therapy with statins showed a neutral effect on mortality in our population. It has been postulated that statins could have a potential role as an adjunct therapy in COVID-19 to mitigate endothelial dysfunction and dysregulated inflammation in patients with COVID-19 . A possible antiviral effect of statins has also been postulated .
A meta-analysis  and two observational studies [13, 50] -one of them in diabetic population - have reported a significant reduction in mortality in patients with COVID-19 who received statins before admission. In another study, in-hospital statin use was linked to a reduced risk of mortality in individuals with COVID-19 . Once again, the mean age of patients included in these studies was significantly younger than in our population, so this potential benefit may not exist in older patients.
Our study has several limitations. First, its observational design does not allow us to determine causal relationships. Additional randomized controlled trials are needed to evaluate confounding factors that were potentially overlooked in our study. Second, our study was conducted in very old patients with diabetes hospitalized with severe SARS-CoV-2 infection and thus its conclusions cannot be extrapolated to other populations with COVID-19. Third, we did not have data on the characteristics of patients’ T2DM, such as glycemic control before hospitalization, duration of diabetes, blood glucose levels during hospitalization, or in-hospital anti-hyperglycemic management. Lastly, the data provided about at-home glucose-lowering drugs did not include information on treatment adherence or treatment duration.