Exploring drugs and vaccines associated with altered risks and severity of COVID-19: a UK Biobank cohort study of all ATC level-4 drug categories

Abstract

BackgroundCOVID-19 is a major public health concern, yet its risk factors are not well-understood and effective therapies are lacking. It remains unclear how different drugs may increase or decrease the risks of infection and severity of disease.MethodsWe studied associations of prior use of all level-4 ATC drug categories (including vaccines) with COVID-19 diagnosis and outcome, based on a prospective cohort of UK Biobank(UKBB). Drug history was based on general practitioner(GP) records. Effects of prescribed medications/vaccinations on the risk of infection, severity of disease and mortality were investigated separately. Hospitalized and fatal cases were categorized as ‘severe’ infection. We also considered different study designs and conducted analyses within infected patients, tested subjects and the whole population respectively, and for 5 different time-windows of prescriptions. Missing data were accounted for by multiple imputation and inverse probability weighting was employed to reduce testing bias. Multivariable logistic regression was conducted which controls for main confounders.ResultsWe placed a greater focus on protective associations here, as (residual) confounding by indication and comorbidities tends to bias towards harmful effects. Across all categories, statins showed the strongest and most consistent protective associations. Significant protective effects against severe infection were seen among infected subjects (OR for prescriptions within a 12-month window, same below: 0.50, 95% CI:0.42-0.60), tested subjects (OR=0.63, 0.54-0.73) or in the general population (OR=0.49, 0.42-0.57). A number of top-listed drugs with protective effects were also cardiovascular medications, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blocker and beta-blockers. Some other drugs showing protective associations included biguanides (metformin), estrogens, thyroid hormones and proton pump inhibitors, among others.Interestingly, we also observed protective associations by numerous vaccines. The most consistent association was observed for influenza vaccines, which showed reduced odds of infection (OR= 0.73 for vaccination in past year, CI 0.65-0.83) when compared cases to general population controls or test-negative controls (OR=0.60, 0.53-0.68). Protective associations were also observed when severe or fatal infection was considered as the outcome. Pneumococcal, tetanus, typhoid and combined bacterial and viral vaccines (ATC code J07CA) were also associated with lower odds of infection/severity.Further subgroup and interaction analyses revealed difference in protective effects in different clinical subgroups. For example, protective effects of flu and pneumococcal vaccines were weaker in obese individuals, while we observed stronger protective effects of statins in those with cardiometabolic disorders, such as diabetes, coronary artery disease, hypertension and obesity.ConclusionsA number of drugs, including many for cardiometabolic disorders, may be associated with lower odds of infection/severity of infection. Several existing vaccines, especially flu vaccines, may be beneficial against COVID-19 as well. However, causal relationship cannot be established due to risk of confounding. While further studies are required to validate the findings, this work provides a useful reference for future meta-analyses, clinical trials or experimental studies.

Metformin therapy and severity and mortality of SARS-CoV-2 infection: a meta-analysis

“…At the level of human endothelial cells, AMPK phosphorylates ACE2 Ser680 and increases ACE2 expression by enhancing its stability. Metformin also enhances the phosphorylation and expression of ACE2 [28]. Phosphorylation produces a conformational and functional ACE2 receptor and decreases the binding of SARS-CoV-2, thus interfering with the entry of the virus into the human cell [7,61].…”

“…Three studies analyzed composite endpoint (mortality and severity) [27,28,40] and metformin was not significantly associated with disease severity and mortality (OR = 0.82, 95% CI: 0.44-1.53, P = 0.025).…”

“…Out of 946 potentially relevant articles, and following application of inclusion criteria, 32 studies were retained including a total of 44306 participants. The included studies were conducted in Austria [14], Belgium [15], China [16][17][18][19][20][21][22][23][24], France [25][26][27], Hong Kong [28], Iraq [29], Italy [30,31], Russia [32]which determines the high relevance of risk factor analysis for outcomes in DM patients to substantiate the strategy for this category of patients. AIM: To assess the effect of clinical and demographic parameters (age, gender, body mass index (BMI, South Korea [33,34], Spain [35,36], UK [37][38][39][40][41] and USA [42][43][44][45].…”

Proton Pump Inhibitor Use Is Not Strongly Associated With SARS-CoV-2 Related Outcomes: A Nationwide Study and Meta-analysis

“…In the updated literature search, 8 studies, 6,7,[12][13][14][15][16] including our current study, investigated the association between current PPI use and risk of SARS-CoV-2 infection. In addition, a recent nationwide study was included alongside a relevant preprint not detected in the initial search.…”