Non-randomized (moderate): Randomization not used or not reported

Open-label or unblinded (moderate): No blinding reported

No power calculation reported (low): No power calculation reported

All-cause mortality was significantly lower with empagliflozin compared with DPP-4 inhibitors (aHR 0.76, 95% CI 0.69 to 0.83). The 3-year risk difference was −0.02 (95% CI −0.03 to −0.01) with a number needed to treat of 47 (95% CI 30 to 66). Results were robust across sensitivity analyses and consistent between RCT-eligible and RCT-ineligible subgroups.

SGLT2 inhibitor initiated at standard doses as prescribed in routine UK primary care for type 2 diabetes management between 2014-2022.

Positive: 1; Negative: 0; No effect: 0; Mixed: 0

Extracted 1 outcome signals across the study

Primary outcome (all-cause mortality) showed a statistically significant and clinically meaningful reduction with empagliflozin vs DPP-4i (aHR 0.76, 95% CI 0.69 to 0.83), with consistent results across all subgroups and sensitivity analyses.

All-cause mortality ↓ by 24% with empagliflozin vs DPP-4 inhibitors (aHR 0.76)

Consistent benefit in RCT-ineligible patients (83% of real-world users)

Study Evidence Depth: High-depth evidence

Empagliflozin was associated with significantly lower all-cause mortality compared with DPP-4 inhibitors across the full study population (adjusted HR 0.76, 95% CI 0.69 to 0.83).

The mortality benefit was consistent regardless of whether patients met EMPA-REG RCT eligibility criteria (p-interaction=0.27), supporting broader real-world use.

Sensitivity analyses using IPTW and E-values confirmed the robustness of findings against potential unmeasured confounding.

Ryan DK, Keogh RH, Williamson E, et al. Enhancing evidence-based care using trial emulation in electronic health records: real-world effects of empagliflozin in people with type 2 diabetes. BMJ Open Diabetes Res Care. 2026;14(1):e005672. doi:10.1136/bmjdrc-2025-005672

Observational design means residual confounding is possible despite rigorous methods.

Cause-specific mortality data were not available, so only all-cause mortality could be assessed.

The study used UK primary care data, so results may not apply to all healthcare settings.

Safety outcomes were not assessed in this analysis.

A trial emulation using UK primary care data from 62,503 people with type 2 diabetes found that empagliflozin reduced the risk of death by 24% compared with DPP-4 inhibitors, with consistent benefits in patients who would have been excluded from the original EMPA-REG trial.

NNT of 47 to prevent one death over 3 years

This ADA guideline recommends SGLT2 inhibitors as part of first-line therapy for type 2 diabetes, particularly in patients with cardiovascular disease, heart failure, or chronic kidney disease, providing clinical context for the expanded use studied in this trial emulation.

Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025

This ESC/EASD guideline recommends SGLT2 inhibitors for cardiovascular risk reduction in patients with type 2 diabetes, supporting the broader prescribing patterns seen in the real-world data analyzed in this study.

ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases (2019)

This NICE guideline recommended SGLT2 inhibitors as dual first-line agents with metformin from 2022, reflecting the policy change that motivated this trial emulation study examining real-world effectiveness beyond original RCT populations.

NICE guideline: Type 2 diabetes in adults: management (NG28)

This ADA/EASD consensus report provides recommendations on SGLT2 inhibitor use in type 2 diabetes management, including cardiovascular risk stratification that informed the guideline changes evaluated in this trial emulation.

Management of Hyperglycemia in Type 2 Diabetes, 2018. A consensus report by the ADA and the EASD

American Diabetes Association resource matched by keyword relevance (type 2 diabetes)

A Guide for People with Type 2 Diabetes | American Diabetes Association

Explore the latest diabetes in America data, including type 2 diabetes statistics, prevalence by age and ethnicity, death rates, and the financial burden of diabetes in the U.S.

Diabetes in America: Prevalence, Statistics, and Economic Impact

Explore diabetes medication management options, from insulin to oral medications, and learn how to choose the best treatments to effectively manage diabetes.

Individuals with type 1 diabetes and those with type 2 diabetes at risk for low blood glucose should take steps to avoid lows when driving.

Insulin resistance is a problem found in people with prediabetes and type 2 diabetes, but people with type 1 diabetes can become insulin resistant, too.

<h4>Importance</h4>Type 2 diabetes (T2D) and liver cirrhosis frequently coexist, creating a high-risk population for adverse outcomes. Patients with both conditions face elevated risks of kidney and cardiovascular complications, yet evidence regarding optimal antidiabetic therapy in this vulnerable population remains limited.<h4>Objective</h4>To evaluate the association of sodium-glucose cotransporter-2 inhibitor (SGLT2i) vs dipeptidyl peptidase-4 inhibitor (DPP4i) use with kidney outcomes, cardiovascular events, and hepatic decompensation in patients with concurrent T2D and liver cirrhosis.<h4>Design, setting, and participants</h4>This nationwide retrospective cohort study utilized data from the Taiwan's National Health Insurance Database between May 2016 and December 2023. Adults with both T2D and liver cirrhosis who initiated either SGLT2is or DPP4is were included.<h4>Exposure</h4>Use of SGLT2is (dapagliflozin, empagliflozin, and canagliflozin) or DPP4is (alogliptin, linagliptin, sitagliptin, saxagliptin, and vildagliptin).<h4>Main outcomes and measures</h4>The primary outcomes were end-stage kidney disease (ESKD), acute kidney injury (AKI), and major adverse cardiovascular events (MACE). Secondary outcomes included individual MACE components and hepatic decompensation events. Inverse probability of treatment weighting was employed to balance baseline characteristics.<h4>Results</h4>Among 24 259 patients (mean [SD] age, 64.68 [11.95] years; 8229 female [33.92%]), 9689 (39.94) received SGLT2is and 14 570 (60.06%) received DPP4is. During a median (IQR) follow-up of 2.3 (1.0-4.0) years, compared with DPP4i use, SGLT2i treatment was associated with significantly reduced risks of ESKD (adjusted hazard ratio [HR], 0.34; 95% CI, 0.25-0.47), AKI (adjusted HR, 0.66; 95% CI, 0.59-0.74), and MACE (adjusted HR, 0.67; 95% CI, 0.62-0.71). Additionally, SGLT2i use was associated with a lower risk of all-cause mortality (adjusted HR, 0.58; 95% CI, 0.53-0.63) and hepatic decompensation events (adjusted HR, 0.65; 95% CI, 0.57-0.74).<h4>Conclusions and relevance</h4>In this cohort study of patients with T2D and liver cirrhosis, the use of SGLT2is was associated with substantially lower risks of adverse kidney, cardiovascular, and hepatic outcomes compared with DPP4is. These findings suggested significant cardiorenal and hepatic protection for SGLT2is in this high-risk population.

SGLT2 Inhibitor Use and Cardiorenal Outcomes in Type 2 Diabetes With Liver Cirrhosis.

<h4>Background</h4>A number of novel antidiabetic drugs have been developed. These drugs include sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is). However, the optimal medication for individuals with type 2 diabetes mellitus (T2DM) and comorbid chronic kidney disease (CKD) has not been established. To this end, this study was conducted to compare specific novel antidiabetic drugs regarding efficacy and safety.<h4>Methods</h4>PubMed, Embase, Cochrane Library, and Web of Science databases were searched for publications dated as of July 9, 2025. Cochrane risk of bias tool version 2.0 (RoB 2.0) was applied to measure the quality of the publications, and R 4.2.2 and Stata 15.1 were used to execute a Bayesian network meta-analysis (NMA). Primary outcomes encompassed major adverse cardiovascular events (MACEs), composite renal outcomes, and all-cause mortality (ACM). Secondary outcomes comprised adverse events (AEs), hypoglycemia, and cardiovascular death.<h4>Results</h4>This NMA incorporated 30 studies, involving 39,844 participants with T2DM and comorbid CKD. The interventions were ranked by performance in various outcomes using the surface under the cumulative ranking curve (SUCRA) values. Sotagliflozin ranked first in reducing MACEs (SUCRA: 90.57%). Empagliflozin ranked first in improving composite renal outcomes (SUCRA: 89.76%) and reducing ACM (SUCRA: 72.38%). Canagliflozin ranked first in reducing AEs (SUCRA: 83.37%). Dapagliflozin + exenatide ranked first in reducing hypoglycemic events (SUCRA: 77.74%). Semaglutide ranked first in reducing cardiovascular mortality (SUCRA: 89.46%).<h4>Conclusion</h4>Novel antidiabetic drugs offer benefits for patients with T2DM and comorbid CKD. However, the optimal intervention varies for different outcomes. Further clinical studies are anticipated to validate these findings.<h4>Systematic review registration</h4>https://www.crd.york.ac.uk/prospero/, identifier CRD420251146144.

Efficacy and safety of novel antidiabetic drugs in patients with type 2 diabetes and chronic kidney disease: a network meta-analysis.

<h4>Aims</h4>This study aimed to compare the real-world effectiveness of dapagliflozin versus empagliflozin in patients with type 2 diabetes (T2D) and to examine prescribing patterns across specialties.<h4>Methods</h4>We conducted a target trial emulation using multi-institutional electronic health records from January 2016 to August 2023, identifying 2649 new users of dapagliflozin and 2046 of empagliflozin. The primary composite outcome was sustained eGFR decline ≥30 %, end-stage renal disease, heart failure hospitalization, or all-cause mortality. Safety outcomes included acute kidney injury, hypoglycemia, urinary tract infection, and fracture. Inverse probability of treatment weighting (IPTW) was used for confounding adjustment, and Cox regression estimated hazard ratios.<h4>Results</h4>After IPTW, 1662 patients remained in each group. No significant differences were found in primary, secondary, or safety outcomes. However, analysis among patients without stable prior ACEI/ARB exposure revealed a higher risk of all-cause mortality with empagliflozin. Dapagliflozin was more often prescribed by cardiologists, while endocrinologists and nephrologists favored empagliflozin.<h4>Conclusions</h4>Dapagliflozin and empagliflozin showed similar cardiorenal and safety outcomes in T2D. However, unstable prior ACEI/ARB use may influence mortality risk with empagliflozin. Prescribing patterns highlight the importance of multidisciplinary care. Further prospective studies are needed.

Comparative effectiveness and prescribing patterns of dapagliflozin vs empagliflozin in type 2 diabetes patients: a target trial emulation.

Although sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiorenal benefits, direct comparisons between dapagliflozin and empagliflozin-the two most commonly used and studied agents in this class-remain limited, particularly in patients with advanced chronic kidney disease (CKD). In the current study, we aimed to compare the cardiorenal effectiveness and safety of dapagliflozin versus empagliflozin in adults with type 2 diabetes (T2D) and stage 3B-5 CKD. We used the TriNetX network and identified adults with T2D and stage 3B-5 CKD newly initiating dapagliflozin or empagliflozin. Following a target trial emulation framework, we applied 1:1 propensity score matching and Cox proportional hazards models to estimate hazard ratios (HRs) for major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), all-cause mortality, and adverse events. After matching, 4,361 participants were included per group. The mean age was 67.6-67.9 years and men comprised 45.3-45.9% with a median follow-up duration of 780-790 days. Dapagliflozin users showed comparable HRs for MAKE (1.04; 95% CI: 0.94-1.16), MACE (1.02; 95% CI: 0.95-1.09), all-cause mortality (0.86; 95% CI: 0.74-1.00), and adverse events (1.03; 95% CI: 0.92-1.14). However, the risk of end-stage kidney disease (ESKD) was higher with dapagliflozin (1.28; 95% CI: 1.11-1.48). We concluded that in adults with T2D and advanced CKD, dapagliflozin and empagliflozin demonstrated comparable cardiorenal effectiveness and safety. Dapagliflozin was associated with a modestly higher ESKD risk, but this finding warrants cautious interpretation and further study given the observational design and potential residual confounding.

Cardiorenal Outcomes of Dapagliflozin vs. Empagliflozin in Advanced Chronic Kidney Disease and Diabetes.

<h4>ABSTRACT</h4>  <h4>Background</h4>  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. <h4>Methods</h4>  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. <h4>Findings</h4>  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). <h4>Interpretation</h4>  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. <h4>Funding</h4>  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. <h4>Evidence before this study</h4>  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. <h4>Added value of this study</h4>  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. <h4>Implications of all the available evidence</h4>  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.

Enhancing evidence-based guidelines using trial emulation in electronic health records: Real-world effects of empagliflozin in people with type 2 diabetes

Limited safety reporting (moderate): Safety reporting depth: not_reported

Non-randomized study (moderate): Randomization not reported or not used

Open-label or unblinded study (moderate): No blinding reported

Empagliflozin reduces mortality in real-world type 2 diabetes patients, including those excluded from pivotal trials

Researchers used UK electronic health records to estimate how well empagliflozin works in real-world patients with type 2 diabetes, including the 83% who would not have qualified for the original EMPA-REG trial. Over up to 9.6 years of follow-up, empagliflozin reduced the risk of death by 24% compared with an older drug class, with consistent benefits across all patient groups.

This was not a randomized trial - it used statistical methods to try to replicate what an RCT would find. The active comparator design (DPP-4 inhibitors vs placebo) helps reduce bias, but unmeasured factors like frailty could still affect results. The study did not examine safety outcomes or other SGLT2 inhibitors besides empagliflozin.

Real-world mortality benefit of empagliflozin in broader type 2 diabetes populations

These findings apply to adults with type 2 diabetes who are candidates for SGLT2 inhibitor therapy, including those without established cardiovascular disease. The results are most relevant to patients managed in primary care settings similar to the UK healthcare system, given the use of THIN database data from 2014 to 2022.

Empagliflozin reduces mortality in real-world type 2 diabetes patients, including those excluded from pivotal trials

BMJ Publishing Group

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