Table 1 Steps to minimise confounding in the EMPRISE study design

Minimising confounding

Key aspects of the EMPRISE study design

PS matching

Patients are 1:1 matched with a “nearest neighbour” based on 140 predefined baseline characteristics (“covariates”)

Covariates include key factors relating to disease severity (such as # antidiabetic medications), comorbidities (such as CVD history) and many other clinical and demographic characteristics

Appropriate comparator choice

The most commonly prescribed DPP-4 inhibitor is the chosen active comparator to empagliflozin, owing to the similar position of DPP-4 inhibitors to SGLT2 inhibitors in the treatment pathway

Using a comparator with a similar position is designed to maximise the similarity of disease severity between cohorts

No overlap between comparators

Patients are excluded if they had received any SGLT2 inhibitor or DPP-4 inhibitor in the year preceding cohort entry, and follow-up is terminated if a patient switches to the comparator

Minimises the potential for immortal time bias

Sequential enrolment

PS matching is performed independently for each enrolment

Ensures that study arms are balanced not just across the full cohort, but also for temporally matched populations

“As-treated” approach

Follow-up captures only outcomes occurring during treatment exposure + 30 days

Minimises bias from confounding events not related to treatment

Assessing balance between cohorts

Data used to independently confirm robustness of PS matching approach

Baseline laboratory scores

A range of laboratory scores at baseline are available for a subset of the population, including Hb1Ac, cholesterol and creatinine levels

These scores are not used for PS matching, and so can provide an independent indication of equivalence between study arms

Sensitivity analyses

In each case, the conclusions regarding HHF benefit with empagliflozin were unchanged

High-dimensional PS matching

PS matching with 100 additional covariates

Alternative comparator

The sitagliptin cohort is replaced with a cohort composed of patients receiving any DPP-4 inhibitor

Subgroup analyses

Subgroup analyses include:

 With/without CVD at baseline

 With/without HF at baseline

 Gender

 Empagliflozin dose

Alternative HHF definition

Broadening the definition of HHF from hospitalisation with HF in the primary discharge position to hospitalisation with HF in any discharge position

Control outcome

An outcome with an expected null finding (flu vaccination)