Real-World Evidence Validates Broad Mortality Benefits for Empagliflozin Beyond Clinical Trials

A landmark study utilizing trial emulation in United Kingdom primary care records has confirmed that the mortality benefits of empagliflozin, originally observed in highly controlled clinical settings, extend to a significantly broader and more diverse real-world population. This research, which analyzed data from over 62,000 adults with type 2 diabetes (T2D) between 2014 and 2022, reveals a disconnect between the stringent eligibility criteria of pivotal randomized controlled trials and the actual patient demographic receiving the drug in routine practice.¹

For pharmacists, these findings provide a robust evidence base for the wider clinical application of sodium-glucose co-transporter 2 (SGLT2) inhibitors, even in patients who would have been excluded from original landmark studies such as the EMPA-REG trial.¹

“The mortality benefit of empagliflozin, originally seen in the EMPA-REG RCT [randomized controlled trial], is also observed in real-world settings, among a broader, more clinically relevant population of people with T2DM,” the study authors said.¹ “Although most individuals prescribed empagliflozin in routine care would not have qualified for the RCT, our findings demonstrate a consistent mortality benefit across both RCT-eligible and RCT-ineligible people.”

Findings of the Real-World Study

The study found that 83.2% of real-world patients prescribed empagliflozin would not have met the eligibility requirements for the original EMPA-REG randomized controlled trial. Although the trial focused on individuals with established atherosclerotic cardiovascular disease, modern clinical practice and updated guidelines from organizations such as the National Institute for Health and Care Excellence have expanded the use of the drug to include those with cardiovascular risk factors but no prior cardiac events.¹

Despite these demographic differences—with real-world users often being older and having a higher percentage of women—the mortality benefit remained consistent, showing an adjusted hazard ratio of 0.76 for all-cause mortality compared to those initiated on dipeptidyl peptidase-4 inhibitors.¹

“By modifying the design of the EMPA-REG RCT to reflect contemporary real-world utilization, we demonstrate that individuals excluded from the RCT, but now receiving treatment with empagliflozin, have comparable treatment effect to those who were represented in the RCT,” the study authors wrote.¹ “This provides a novel evidence base for people with T2DM, many of whom are underrepresented and ultimately underserved by RCTs.”

About Empagliflozin in Cardiometabolic Spaces

The physiological mechanism underpinning these broad benefits lies in the specific way empagliflozin interacts with the kidneys. As an aryl-C-glucoside, empagliflozin binds to SGLT2 transporters in the luminal membrane of the early proximal tubule, blocking the reabsorption of approximately 50% to 60% of filtered glucose.^2,3

This class of drugs, often referred to as gliflozins, is highly selective, with empagliflozin demonstrating a 2700-fold greater affinity for SGLT2 over SGLT1, which minimizes intestinal adverse effects like diarrhea. Beyond glucose control, researchers suggest that the drug’s cardioprotective effects may be linked to off-target inhibition of cardiac sodium-proton exchangers, which helps lower intracellular sodium and calcium levels in heart tissue.³

From a clinical management perspective, the dosage for empagliflozin typically begins at 10 mg once daily in the morning, with a maximum recommended dose of 25 mg. Pharmacists must remain vigilant regarding drug interactions, particularly when empagliflozin is coprescribed with diuretics like furosemide or hydrochlorothiazide, as this can increase the risk of dehydration, low blood pressure, and fainting. Furthermore, while the drug offers significant protection against heart failure and the progression of chronic kidney disease, it requires careful patient counseling regarding potential adverse effects.²

Safety monitoring is a vital component of the pharmacist's role in SGLT2 inhibitor therapy.¹ Patients should be educated on the symptoms of genital yeast infections and urinary tract infections, which are among the more common adverse effects. Of greater concern are rare but life-threatening conditions such as diabetic ketoacidosis and necrotizing fasciitis of the perineum, also known as Fournier gangrene. Patients must be advised to seek immediate medical attention if they experience fever, unusual pain, or swelling in the genital area or if they develop symptoms of ketoacidosis such as nausea, trouble breathing, or a fruit-like breath odor.²

Conclusion

Ultimately, this real-world data reinforces the value of empagliflozin as a versatile tool in the management of T2D, heart failure, and chronic kidney disease. By demonstrating that the mortality benefits persist across a wider range of metabolic and cardiovascular profiles, the study supports the current trend toward more inclusive prescribing practices.^1,2

For the pharmacy profession, these insights highlight the importance of balancing the drug's expansive benefits with rigorous monitoring for serious side effects and drug-drug interactions in an increasingly complex patient population.^1,2

READ MORE: Diabetes Resource Center

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REFERENCES

1. 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. Published 2026 Feb 9. doi:10.1136/bmjdrc-2025-005672

2. Mayo Clinic. Empagliflozin (oral route). Updated February 1, 2026. Accessed February 10, 2026. https://www.mayoclinic.org/drugs-supplements/empagliflozin-oral-route/description/drg-20113010

3. Wright EM. SGLT2 Inhibitors: Physiology and Pharmacology. Kidney360. 2021 Sep 17;2(12):2027-2037. doi: 10.34067/KID.0002772021. PMID: 35419546; PMCID: PMC8986039.