Enhancing Evidence-Based Care Using Trial Emulation in Electronic Health Records: Real-World Effects of Empagliflozin in People with Type 2 Diabetes.

Background There is growing interest in widening the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) to all people with type 2 diabetes mellitus (T2DM). However, pivotal randomized controlled trials (RCTs) evaluated these drugs only in highly selected populations, often lacking generalizability to real-world populations. Understanding the effects of SGLT2i in populations where RCT evidence may be lacking is essential to help inform guideline development. To address this, we estimated the effect of empagliflozin in real-world users, many of whom would not have been eligible for the pivotal EMPA-REG RCT.Methods We designed a trial emulation in UK primary care data, based on the EMPA-REG RCT, to assess the effect of empagliflozin in a more clinically relevant population. Adults with T2DM initiating empagliflozin (intervention) or dipeptidyl peptidase-4 inhibitors (active control) between January 1, 2014 and December 31, 2022 were included. Eligibility was extended to both RCT-eligible and RCT-ineligible individuals. The effect of empagliflozin on all-cause mortality was estimated using an adjusted Cox proportional hazards model, with stratified analyses by RCT eligibility.Findings The majority of people prescribed empagliflozin would not have met the EMPA-REG RCT eligibility criteria (11,011/13,239, 83.2% RCT-ineligible). During follow-up, all-cause mortality occurred in 551 out of 13,239 (4.2%) in the empagliflozin group and 6,589 out of 49,264 (13.4%) in the active control group (adjusted HR 0.76, 95% CI 0.69 to 0.83). There was no evidence of differential treatment effect by RCT eligibility status (p-interaction=0.27).Interpretation Patients prescribed empagliflozin in real-world settings differ substantially from those enrolled in the EMPA-REG RCT. Using electronic health records, we demonstrate that the mortality benefit observed in EMPA-REG extends to a broader, more diverse real-world population, including those excluded from the original RCT. These findings provide a novel source of real-world evidence supporting the wider use of empagliflozin in routine clinical practice.