Empagliflozin More Effective to Reduce Risk of Heart Failure Hospitalization vs DPP-4 Inhibitors, GLP-1 Receptor Agonists

In a real-world analysis spanning 5 years, the sodium-glucose contransporter-2 (SGLT-2) inhibitor empagliflozin demonstrated a significantly greater reduction in relative risk for hospitalization for heart failure (HHF) than either dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists in adults with type 2 diabetes (T2D).

The findings, from the EMPRISE study, were presented at the American Diabetes Association (ADA) 82nd Scientific Sessions held June 4-7, in New Orleans, LA.

Compared with the 2 other classes of glucose-lowering therapies used in routine care of T2D, empagliflozin treatment was associated with relative risk reductions in HHF of >50% vs DPP-4 inhibitors and of nearly 40% vs GLP-1 receptor agonists.

The analysis also found empagliflozin treatment associated with a 12% reduction in risk for a composite cardiovascular (CV) outcome vs DPP-4 inhibitors and a 40% reduction in relative risk reduction of all cause mortality in a group of Medicare recipients.

In the US there are now more than 29 million people diagnosed with T2D and nearly one-quarter (22%) may also have HF, said co-investigator Elisabetta Patorno, MD, DrPH, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital and associate professor of medicine, Harvard Medical School, in a statement. “It is critical that healthcare professionals caring for this population have treatments that demonstrate cardiovascular effectiveness in routine care.”

EMPRISE (the Empagliflozin Comparative Effectiveness and Safety) was a 5-year monitoring program designed to assess the safety and efficacy of empagliflozin during the first 5 years of use and to complement data from the landmark EMPA-REG OUTCOME trial by comparing the SGLT-2 inhibitor in real-world clinical use with DPP-4 inhibitors and GLP-1 receptor agonists, the statement explains.

For both comparisons, EMPRISE investigators used data from Medicare and 2 US commercial claims databases (Optum Informatics, IBM MarketScan) from 2014-2019 (2018 for Medicare) and created propensity matched cohorts for each set of comparisons.

Empagliflozin and DPP-4 inhibitors

For the comparison of empagliflozin vs DPP-4 inhibitors, Patorno and colleagues identified 190 226 patients aged ≥18 years T2D who initiated either empagliflozin or a DPP-4 inhibitor and followed them for 5 years. The primary outcome of interest was incidence of HHF in primary (HHF-primary) or in any discharge positions (HHF-broad), a composite of myocardial infarction (MI) and stroke, and all-cause mortality, assessed in Medicare recipients only.

In this analysis, the safety outcomes of interest were the incidence of lower-limb amputations, nonvertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), and renal and bladder cancers.

After propensity score matching that adjusted for 143 baseline covariates, investigators estimated pooled hazard ratios (95% confidence interval). They found that use of empagliflozin compared with that of DPP-4 inhibitors was associated with:

• Reduced risk of HHF (HHHF-specific: 0.47 (0.41, 0.55); HHF-broad: 0.67 (0.62, 0.72)]
• Reduced risk of all-cause mortality (HR, 0.56 [95% CI, 0.46-0.68])
• Similar risk of the composite of MI or stroke (HR, 0.92 [95% CI, 0.84-1.02])

The safety analysis found that empagliflozin use was associated with a reduced risk of AKI (HR, 0.73 [95% CI, 0.68-0.78]), an increased risk of DKA (HR, 1.88 [95% CI, 1.51-2.34]), and a similar risk of lower-limb amputations, fractures, and renal and bladder cancers compared with use of DPP-4 inhibitors.

Empagliflozin and GLP-1 RA

When comparing empagliflozin against GLP-1 receptor agonist use, the EMPRISE study team identified from the databases mentioned, adults aged ≥18 years T2D who initiated either empagliflozin vs a GLP-1 RA or empagliflozin vs liraglutide specifically. Primary outcomes of interest after 5 years for this analysis were HHF, MI, stroke, and all-cause mortality, this last examined only in participants in the Medicare database.

After 1:1 propensity-score matching, investigators identified 105 955 pairs of empagliflozin vs GLP- receptor agonist initiators and 72 498 pairs of empagliflozin vs liraglutide initiators. When empagliflozin treatment was compared to that with GLP-1 receptor agonists at 5 years, it was associated with:

• Lower risk of HHF (HR, 0.62 [95% CI, 0.53-0.71])
• Similar risk of MI (HR, 0.95 [95% CI, 0.85, 1.07])
• Similar risk of stroke (HR, 1.09 [95% CI, 0.94-1.27])

The researchers found similar results whether or not participants had a history of cardiovascular disease.

When they compared new empagliflozin users to new liraglutide users, the team found risk estimates similar to those seen with GLP-1 receptor agonists overall as well as across subgroups.

“We are pleased to present the final data from EMPRISE in the U.S., which encompasses information from nearly 500,000 adults in a real-world care setting,” said Leonard Glass, MD, vice president of Diabetes Global Medical Affairs at Eli Lilly and Company, in the same statement.

“As we strive to help fill unmet treatment needs, this study reinforces our longstanding commitment to people living with cardio-metabolic conditions. Building upon our robust clinical trial program, EMPRISE highlights the potential of Jardiance to improve health outcomes in routine clinical practice.”

References

Htoo PT, Tesfaye H, Paik JM, et al. Cardiovascular effectiveness of empagliflozin vs glucagon-like peptide-1 receptor agonists or liraglutide in the EMPRISE study. Diabetes 2022;71(Supplement_1):179-OR

Htoo PT, Tesfaye H, Paik JM, et al. Effectiveness and safety of empagliflozin in routine care: results from the empagliflozin comparative effectiveness and safety (EMPRISE) study. Diabetes 2022;71(Supplement_1):1079-P