Enhancing evidence-based guidelines 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 randomised controlled trials (RCTs) evaluated these drugs only in highly selected populations, often lacking generalisability 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 a 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 1 Jan 2014–31 Dec 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 (11011/13239, 83.2% RCT-ineligible). During follow-up, all-cause mortality occurred in 551/13239 (4.2%) of the empagliflozin group and 6589/49264 (13.4%) of the active control group (adjusted HR 0.76, 95% CI 0.69–0.83). 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.

Funding

DKR, NIHR Doctoral Fellow (NIHR304689), is funded by the NIHR for this research project. RHK is funded by UK Research and Innovation (Future Leaders Fellowship). EW is funded by a Wellcome Senior Research Fellowship (grant number 224485/Z/21/Z). RTL is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the UCL British Heart Foundation Accelerator (AA/18/6/34223), the MRC/NIHR Rare Disease Research UK Cardiovascular Initiative.

Evidence before this study

• Randomised controlled trials (RCTs), including the seminal EMPA-REG RCT, have shown that empagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i), significantly reduces mortality in people with type 2 diabetes (T2DM) and established atherosclerotic cardiovascular disease.

• There is growing interest in expanding SGLT2i use to broader populations, with draft UK National Institute for Health and Care Excellence (NICE) 2025 guidelines proposing it as first-line therapy for all people with T2DM, in combination with metformin.

• Given the growing divergence between RCT evidence and proposed universal use of SGLT2i in T2DM management, the real-world effectiveness of empagliflozin, particularly among patients under-represented in RCTs, remains uncertain.

Added value of this study

• Using the trial emulation framework in UK primary care data, we demonstrate that the population receiving empagliflozin in current practice already differs substantially to the population enrolled in the EMPA-REG RCT.

• We demonstrate that relaxing the stringent RCT eligibility criteria imposed by EMPA-REG RCT did not alter the treatment effect in real-world populations, with strong evidence of a mortality benefit in people, regardless of RCT eligibility status.

Implications of all the available evidence

• These results support broader use of empagliflozin in T2DM management, beyond the eligibility criteria of landmark RCTs.

• These findings provide critical real-world evidence supporting a universal SGLT2i strategy in T2DM management, which is of direct relevance to current guideline deliberations.