This large-scale real-world data (RWD) population-based case–control study has shown that enalapril and candesartan reduced the risk of severity of COVID-19 (lower risk of hospitalization and mortality). Given that these effects are not found for all ACEIs/ARBs, enalapril and candesartan, could be the active ingredients to consider within these pharmacological groups in future COVID 19 emergency situations, and could even be candidate medications (Asiimwe et al. 2022) for use against other emerging viral diseases.

The results of our study indicate that, as a group, ACEIs/ARBs appear to be associated with a reduction in severity (mortality and hospitalization), something that would be consistent with the results of the most recent meta-analyses (Huang et al. 2023; Meng et al. 2020) performed for these groups of drugs. As in the case of other pharmacological groups (Visos-Varela et al. 2023), however, an appreciable degree of variability was detected in the effects depending upon the active ingredient, a finding that may prove highly relevant in clinical practice.

While a great number of studies have analysed COVID-19 outcomes by subgroups, very few have done so by active ingredient. Our results, as with studies on telmisartan, losartan, valsartan (Gnanenthiran et al. 2022) and ramipril (Ajmera et al. 2021; Asiimwe et al. 2022), showed no significant differences in terms of the effect of chronic use on mortality and hospitalization. Even so, ours is the first study to show that enalapril is associated with a decreased risk of hospitalization (aOR 0.72 [95% CI 0.61–0.85]), mortality (aOR 0.59 [95% CI 0.38–0.92]) and susceptibility (aOR 0.86 [95% CI 0.79–0.94]). We feel that there is little likelihood of this finding being due to chance or to some type of bias arising from the internal consistency between the results of the different outcomes.

In the case of candesartan, our results show a lower risk of hospitalization (aOR 0.73 [95% CI 0.56–0.95]) and progression (aOR 0.73 [95% CI 0.56–0.95]), which would be in line with the clinical trial conducted by Lukito et al. (Lukito et al. 2021). In addition, our large sample size -something that is difficult to attain in clinical trials- enabled us to identify its association with a decrease in mortality (aOR 0.36 [95% CI 0.17–0.75]).

We feel that our findings are not only statistically significant, but also clinically relevant. Hence, the reductions in mortality of 41% (95%CI: 8%-62%) and 64% (95%CI: 25%-83%) associated with prior exposure to enalapril and candesartan respectively could indicate that these active ingredients might well be the ACEIs/ARBs of choice in a COVID-19 outbreak situation.

Enalapril, unlike other ACEIs, does not display adverse immunological effects that could, in part, account for the effects found in our study. Furthermore, enalapril has an anti-inflammatory effect, on blocking the degradation of bradykinin (vasodilator substance), which inhibits the inflammatory cascade (Pedrosa et al. 2021; Ridgway et al. 2022) associated with the harm caused by SARS-CoV-2 infection (Pedrosa et al. 2021). This mechanism could explain the appreciable decrease in risk of severity (hospitalisation and mortality) and susceptibility, as compared to other active ingredients in the same pharmacological subgroup.

The reduction in risk of severity and progression of the virus brought about by candesartan might be determined by: (i) its anti-inflammatory effects on the lung (Dasu et al. 2009; Pedrosa et al. 2021), thanks to the fact that it binds with high affinity to the AT1 receptor (Ridgway et al. 2022), and thus dissociates more slowly (Tamargo et al. 2006) and inhibits oedema and cytokine release; and (ii) its in vitro antiviral effect (Elkahloun and Saavedra 2020), due to its chemical structure (bisphenyl tetrazoles (Liu et al. 2006; Ridgway et al. 2022)).

Our results for enalapril and candesartan, along with their mechanisms of action, suggest that, among ACEIs and ARBs, these two active ingredients could be drugs of choice in the face of new SARS-CoV-2 pandemics or outbreaks and could also play a similar role in the face of threats by other emerging viral infections, due to:

their high effect magnitude observed in our data for the various outcomes;

their safety and efficacy profile being similar to that of other active ingredients in the group;

their low cost, a factor that might be especially important for low-and middle-income countries in which access to vaccines and antivirals is difficult; and,

their potential effect on viral diseases with an important inflammatory component, e.g., influenza, zika (Loe et al. 2019), ebola, pneumonia (Fedson 2016) and dengue (Hernández-Fonseca et al. 2015), something that would suggest the need for more studies to be conducted into their potential effect on such diseases.

Our study design has a number of strengths: (1) in a region of approximately 3 million inhabitants it included all cases with positive diagnosis of COVID-19 in 2020, thus eliminating the possibility of selection bias; (2) for the first time, it made it possible to assess the effect of ambulatory use of antihypertensives on the entire natural history of COVID-19, ranging from susceptibility, through progression and hospitalization, to mortality; (3) our large sample size enabled us to assess the effects of each active ingredient, a key factor, since our initial hypothesis postulated that each active ingredient could display different effects; (4) our study allowed us to adjust for many confounding variables, such as socio-demographic factors, comorbidities, and use of other medications; (5) exposure was measured on the basis of administrative databases, something that reduces the risk of misclassification, though there may be a residual effect due to incomplete adherence to the treatment (Lam and Fresco 2015); (6) the models used and our results proved to be very robust, since the subanalysis of hypertensive patients (Patel and Verma 2020) showed very slight or negligible variations compared to the overall results. In view of our findings for enalapril and candesartan, however, we feel that if there had been a lack of therapeutic adherence, this would underestimate the associations, which could, in turn, indicate that the beneficial effect might be even greater.

Important limitations must also be considered when interpreting the results of our study. Firstly, by virtue of it being an observational study with secondary databases, one cannot rule out that there may be variables which acted as confounding factors that were not measured or may have been misclassified. In the variables that were indeed collected (e.g., indication and pathology), the level of severity was not available to us, and there could thus be a risk of a certain degree of residual confounding. Secondly, the lack of matching in the susceptibility and progression substudies could be perceived as a limitation. Yet, according to Rose and Rothman, (Rose & Laan 2009; Rothman et al. 2008), lack of matching in case–control studies only reduces efficacy but has no influence on risk of bias. Thirdly, the data used pertain to 2020, a time when the alpha variant was predominant, and our results should thus be extrapolated with caution for any other type of variant. Fourthly, during the first months of the pandemic, there was a limited availability of diagnostic tests, which might possibly have resulted in some COVID-19 non-PCR + subjects in realty being asymptomatic COVID-19 subjects. Finally, one might think that the results obtained from ACEIs/ARBs on in-hospital mortality could be affected by in-hospital treatment. However, we have no reason to think that the in-hospital treatment received depends on which type of ACEIs/ARBs they take. Furthermore, patients prescribed an ACEIs/ARBs would be expected to have a higher cardiovascular risk, associated with worse COVID-19 outcomes, but despite this, the results suggest that these drugs decrease the risk.

In conclusion, the COVID-19 pandemic has led us to reflect on the need to use drug-repurposing as a strategy to combat global public health threats. The results of this large-scale RWD study suggest that enalapril and candesartan are associated with a sizeable reduction in risk of severe COVID19 outcomes. If these results were repeated with other databases and replicated in clinical trials, we feel that, given the magnitude of the effects found, this finding could well be relevant for preventing the impact of COVID-19. Moreover, our results, along with those of in vivo and in vitro studies, suggest the need for more research to evaluate these drugs’ potential effect against viral diseases with a major inflammatory component, present or future.