Combined treatment with both a GLP-1 receptor agonist (GLP-1RA) and an SGLT2 inhibitor was linked to lower all-cause mortality and a lower risk for some cardiovascular outcomes, new research showed.

These findings, from a large German health database, “suggest that sustained concurrent use of both drug classes may offer meaningful clinical advantages in routine practice, though the findings for specific secondary outcomes warrant further investigation,” Gregor A. Maier, MSc, of the Institute for Biometrics and Epidemiology, German Diabetes Center, Düsseldorf, Germany, and colleagues wrote in their study, published online in Diabetes, Obesity and Metabolism.

The study included 220,043 individuals who initiated SGLT2 inhibitors, of whom 2660 were also using GLP-1RAs at baseline. Of the other 217,383, a total of 22,781 were later prescribed a GLP-1RA. After matching, there were a total of 21,664 combination SGLT2i plus GLP-1RA users, and the same number of SGLT2i-only users. Study participants were enrolled between 2013 and 2023, with follow-up through 2024. The primary outcome was all-cause mortality.

Among combination users, the most frequently prescribed combinations were dulaglutide plus empagliflozin (25%), dulaglutide plus dapagliflozin (24%), semaglutide plus dapagliflozin (18%), and semaglutide plus empagliflozin (14%).

Combination therapy had a 29% lower risk for all-cause mortality than SGLT2i-only users (hazard ratio [HR], 0.71 [95% CI, 0.63-0.80]; incidence rate [IR], 13.4 vs 18.6 per 1000 person-years [py]) over a median follow-up of 1.3 years.

Those treated with combination therapy also had a lower risk for the cardiovascular composite outcome (HR, 0.81 [95% CI, 0.74-0.88]; IR, 24.4 vs 29.9 per 1000 py) and heart failure (HR, 0.78 [95% CI, 0.68-0.89]; IR, 10.0 vs 12.2 per 1000 py).

Other secondary outcomes were also lower with the combination therapy, including myocardial infarction (HR, 0.95; IR, 6.2 vs 6.5 per 1000 py) and stroke (HR, 0.86; IR, 6.1 vs 6.9 per 1000 py) but did not achieve statistical significance. Nephropathy was increased with the combination therapy (HR, 1.23; IR, 1.0 vs 0.8 per 1000 py), but renal failure was lower (HR, 0.9; IR, 3.2 vs 3.4 per 1000 py); neither were significant.

The effects were similar in subgroups and sensitivity analyses.

“Our findings align with UK data showing a 27% lower risk of all-cause mortality (HR, 0.73; 95% CI, 0.52-1.01) in individuals who, for the most part, had poor glycemic control (HbA1c > 8%). Importantly, we observed similar benefits in a German population with generally better glycemic control, suggesting the advantages of combination therapy may extend beyond individuals with poorly controlled diabetes,” Maier and colleagues wrote.

Potential Benefits and Harms

Asked to comment, Richeek Pradhan, MD, PhD, assistant professor at the Centre for Medicine Use and Safety, Monash University, Parkville, Victoria, Australia, told Medscape Medical News, “Biologically, GLP-1RAs and SGLT2 inhibitors provide cardio protection through different mechanisms, so their synergy is plausible.”

“This paper adds to the evidence that combination of these meds may provide benefits in addition to the use of SGLT2 inhibitors alone, though we have to be careful about the observational nature of the current literature and lack of evidence regarding potential harms of such combinations,” he said.

Pradhan, who is a pharmacologist and pharmacoepidemiologist by training, also pointed out, “In many health systems, GLP-1RAs can only be prescribed to individuals who fail on other medications, so a combination use may not be immediately available. Moreover, in other systems requiring significant out of pocket payments, affording a combination of these relatively expensive medications can be potentially difficult.”

“As always,” he added, “the treatment decisions should be personalized. Using these drugs together means not just potential benefits, but also potentially compounding harms. Many of the patients who are at higher risk of [cardiovascular disease] and who could theoretically benefit from combinations are also frail, so combining these relatively potent drugs could also, at least theoretically, add to troublesome side effects.”

“Examining the risks of GLP-1RA-SGLT-2 inhibitor combinations need to be part of future research and treatment decision-making,” Pradhan concluded.

The German Diabetes Center was funded by the German Federal Ministry of Health, the Ministry of Culture, and Science of the State of North Rhine-Westphalia; and grants from the German Federal Ministry of Education and Research to the German Center for Diabetes Research. Maier reported having no further disclosures. One coauthor reported the receipt of consulting fees for attending educational sessions by Novo Nordisk outside of the topic of the current work, and another received honoraria for biostatistical education from Berlin Chemie. Pradhan reported having no disclosures.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and diaTribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.