Electronic health records can be used to track diagnoses and drug prescriptions in large heterogeneous populations over time. Coupled with recent advances in causal inference from observational data, these records offer new opportunities to emulate clinical trials and identify potential targets for drug repositioning. Here, we run a hypothesis generating cohort study of Danes aged 50 to 80 years from 2001 to 2015 (n = 2,512,380), covering a total of 23,371,354 years of observations. We examine prescription drugs at ATC level-4 and their effect on 9 major disease outcomes. Using Bayesian time-varying Cox regression and longitudinal minimum loss estimation, our analysis successfully reproduces known drug-disease associations from clinical trials, such as the reduction in the 3-year absolute risk of death associated with Statins (ATC:C10AA) -0.8% (95% CI =[-1.2%, -0.5%]) and -0.8% (95% CI =[-1.3%, -0.2%]) for females and males, respectively. Additionally, we discovered novel associations that suggest potential repositioning opportunities. For instance, Statins were associated with a reduction in the 3-year absolute risk of dementia by -0.3% (95% CI =[-0.5%, -0.1%]) for females and -0.2% (95% CI =[-0.4%, 0.1%]) for males. Furthermore, Biguanides (ATC:P01BB) stands out as a particularly interesting candidate with absolute risk reductions across various outcomes. In total, we identified 76 potential drug-disease pairs for further investigation. However, it should be stressed that the emulation of clinical trials here is solely of hypothesis generating nature and identified effects need to be corroborated with additional evidence, preferably from RTCs, as the risk of confounding by indication in this study is substantial. In summary, this study provides a large-scale screen of prescribed drugs and their effect on major debilitating disease in the Danish health registries. This provides an additional source of information that can be used in the search for possible repositioning candidates.

SB received personal compensation for managing board memberships at Intomics and Proscion and is a scientific advisory board member of Biocenter Finland, Health Data Research UK, the Finnish Center of Excellence in Complex Disease Genetics, ELIXIR Node (Luxembourg), Lund University Diabetes Centre (Lund, Sweden), and SciLifeLab (Stockholm, Sweden). SB reports stocks in Intomics, Hoba Therapeutics Aps, Novo Nordisk, Eli Lilly and Lundbeck. All other authors declare no competing interests.

This work was supported the Novo Nordisk Foundation under grants NNF17OC0027594 and NNF14CC0001.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The use of the Danish National Registries was conducted under the Danish Data Protection Act. Furthermore, the analysis was conducted under the information security and data confidentiality policies of Statistics Denmark, which is the Danish National Statistical Institution.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Danish registry data are available for use in secure, dedicated environments via application to the Danish Patient Safety Authority and the Danish Health Data Authority via https://sundhedsdatastyrelsen.dk/da/english/health_data_and_registers/research_services/a pply.