Whichever of the two flagship diabetes drugs a patient started on, adding the other one lowered their heart risk more than adding an older pill. That is the finding of the EMPRISE study ↗, published July 12 in Cardiovascular Diabetology, and it is the closest thing yet to real-world evidence for pairing the two classes that have dominated diabetes care for a decade.
The two classes are the SGLT2 inhibitors, of which empagliflozin (sold as Jardiance) is the most prescribed, and the GLP-1 receptor agonists, the Ozempic and Wegovy family ↗. SGLT2 inhibitors are pills that make the kidney dump excess sugar into the urine. GLP-1 drugs, most given by injection, blunt appetite and prompt the pancreas to release insulin when blood sugar is high. Both cut heart attacks and deaths in their own large trials. What almost no trial has tested directly is what happens when a patient takes both.
What the study did
The researchers ran what is called a target-trial emulation, a method that uses insurance records to mimic the randomized trial nobody has run. They pulled adults with type 2 diabetes from US Medicare and two commercial claims databases, Optum Clinformatics and MarketScan, covering 2013 through 2022. Then they built two head-to-head comparisons, one for each starting drug.
In the first, everyone began on empagliflozin. Some then added a GLP-1 drug, others added a DPP-4 inhibitor, an older and gentler class that raises the body's own incretin hormones. The empagliflozin-plus-GLP-1 group had a lower rate of major heart events, meaning heart attack, stroke, or death from any cause. Their hazard ratio was 0.81 (95 percent confidence interval 0.67 to 0.97), which translates to roughly a fifth fewer such events. The gap on heart failure hospitalization or death was wider still, a hazard ratio of 0.61 (0.48 to 0.77), close to a 40 percent reduction.
In the second comparison, everyone began on a GLP-1 drug. Some added empagliflozin, others added a sulfonylurea, one of the oldest diabetes pills, which squeezes more insulin out of the pancreas but does nothing for the heart. Adding empagliflozin beat adding a sulfonylurea on major heart events (hazard ratio 0.68, or about a third fewer) and on heart failure or death (0.62). To keep the numbers grounded, the authors also reported absolute differences: the combination arms had between about 4 and 7 fewer heart failure or death events per 1,000 patients each year.
Why the direction matters
The result is symmetric, and that symmetry is the story. It did not matter which drug the patient took first. In both directions, the arm that added the second modern class did better than the arm that reached for an older, cheaper pill. That is the pattern you would expect if the two drugs protect the heart through separate mechanisms that stack rather than overlap, which is what cardiologists have suspected but could not show without a trial that pairs them.
The method has real limits, and the authors do not hide them. Claims data cannot see everything a trial can, and the analysis leaned on more than 130 baseline variables and propensity-score weighting to make the compared groups resemble each other. People prescribed two newer, pricier drugs differ from people left on an old sulfonylurea in ways no covariate list fully captures. A hazard ratio from insurance records is a strong hint, not a verdict.
Still, the size and consistency are hard to wave away. The GLP-1 receptor ↗ sits at the center of peptidemodel's metabolic corpus, alongside the injectable exemplars semaglutide ↗ and dulaglutide ↗ that make up most GLP-1 prescribing in a dataset like this one. We have covered the class turning up heart benefits in patients the big outcome trials left out ↗. EMPRISE extends that pattern in a different direction: not a new population, but a new pairing. The next question is whether a randomized trial will bother to confirm what the claims already suggest, or whether prescribers will move first.