Aims: Randomized controlled trials (RCTs) have high internal validity but often have limited generalizability. To our knowledge, there have been no previous studies emulating RCTs using real-world data to evaluate the risk of major adverse cardiovascular events (MACE) among patients with type 2 diabetes mellitus (T2DM) treated with long-acting insulin analogues.
Methods: We emulated the DEVOTE trial of insulin degludec vs. glargine among patients with T2DM using data from the United Kingdom's Clinical Practice Research Datalink. DEVOTE eligible and ineligible subpopulations were created. Cox proportional hazards models with inverse probability of treatment weighting were used to estimate hazard ratios (HRs) and corresponding confidence intervals (CIs) for MACE comparing new users of insulin degludec to new users of insulin glargine overall and in the eligible/ineligible subpopulations.
Results: There were 10 430 patients in the overall population, 5280 in the DEVOTE eligible population, and 5150 in the DEVOTE ineligible population. The overall (HR: 1.36, 95% CI: 0.83, 1.86) and DEVOTE eligible populations (HR: 1.07, 95% CI: 0.63, 1.58) were compatible with findings from the DEVOTE trial (HR: 0.91, 95% CI: 0.78, 1.06) for the risk of MACE. Due to a low number of events, the DEVOTE ineligible population had deviations in point estimates and wider CIs (HR: 2.19, 95% CI: 0.30, 3.83).
Conclusion: The risk of MACE among patients with T2DM newly prescribed insulin degludec compared to insulin glargine was consistent between the overall population and the DEVOTE eligible subpopulation, while the DEVOTE ineligible population had discrepant point estimates.
Keywords: cardiovascular outcome trials; real‐world data; type 2 diabetes.
Patients enrolled in randomized controlled trials (RCT) are often different from the patients who are taking antidiabetic medications in everyday clinical settings. Our study emulated the DEVOTE trial to compare patient characteristics and risk of developing cardiovascular events among patients with type 2 diabetes taking either insulin glargine or insulin degludec for the first time. We used patients from primary care practices in the United Kingdom from 2014 to 2018 and applied the eligibility criteria of the trial. We included confounders and reweighted our populations to make the two treatment groups similar in terms of patient characteristics. We found that only 50% of the primary care patients would have been eligible for the trial, with differences in patient characteristics such as age, comorbidities and comedications. The overall primary care population and the population eligible for the trial had similar clinically important risk of developing cardiovascular outcomes as the DEVOTE trial. The population ineligible for the DEVOTE trial had inconclusive results.
© 2026 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.