EMPRISE: Interim Results Support Real-World Efficacy, Safety of Empagliflozin

Empagliflozin was again the subject of interest in the EMPA-REG OUTCOME trial that showed its efficacy in patients with type 2 diabetes. The article was published by BreakingMED on July 14, 2021 and looked at further data from the EMPRISE study with some very positive results. Click here to view the original article and obtain your CME/CE credit.

Treating patients with type 2 diabetes with empagliflozin significantly reduced the risks of all-cause mortality, hospitalization for heart failure, a composite endpoint of myocardial infarction, stroke, and all-cause mortality, and acute kidney injury requiring dialysis, according to results from three interim analyses of real-world data from the EMPRISE study.

Previously, researchers of the EMPA-REG OUTCOME study demonstrated the cardiovascular benefits of treatment with empagliflozin to standard care in patients with type 2 diabetes. Empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, was superior to placebo in improving glycemic control and reducing cardiovascular events in patients with type 2 diabetes and cardiovascular disease.

In this study of over 7,000 subjects, empagliflozin (10 or 25 mg) reduced the composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke compared with placebo (10.5% versus 12.1%, respectively; P=0.04). This reduction was driven by lower cardiovascular mortality in the treatment group (3.7% versus 5.9%; P˂0.001).

Empagliflozin also significantly lowered the risk of hospitalization for heart failure compared with placebo (2.7 versus 4.1%, respectively; P=0.002), for a relative risk reduction of 35%.

Following on the heels of the EMPA-REG OUTCOME study, the EMPagliflozin comparative effectiveness and SafEty (EMPRISE) trial is an ongoing real-world study in over 300,000 patients with type 2 diabetes from 12 countries that was designed to assess the use of empagliflozin compared with DPP-4 inhibitors (DPP-4i) or GLP-1 receptor agonists, as well as its real-world cardiovascular efficacy, safety, and healthcare use in patients with type 2 diabetes with and without cardiovascular disease.

Three interim analyses of EMPRISE—which included European data, as well as data from Israel and East Asia—were presented at the ADA 2021 Annual Meeting detailing interim results. In the first of these, Elisabetta Patorno, MD, of Brigham and Women’s Hospital, Boston, and colleagues presented results on the cardiovascular effectiveness of empagliflozin versus DPP-4is in patients with and without cardiovascular disease.

Using data from 2014-2018 from Medicare and two U.S. commercial claims datasets, they identified patients with type 2 diabetes with and without cardiovascular disease who were initiated on treatment with empagliflozin or a DPP-4i.

After a mean follow-up of 6.3 months, reductions in the risk of hospitalizations for heart failure were greater with empagliflozin compared with DPP-4i in patients with and without cardiovascular disease (HE: 0.71 versus 0.55, respectively), as were reductions in mortality (HR: 0.53 versus 0.46). Patients with CVD had larger risk reductions, but a similar risk of ASCV events, such as myocardial infarction or stroke.

In the second study, Patorno and colleagues studied the comparative safety of empagliflozin in routine care patients. These interim results showed that over a mean follow up of 6.3, patients treated with empagliflozin had a similar risk of lower-limb amputations and fractures compared with DPP-4is, increased risk of diabetic ketoacidosis hospitalization (HR: 2.01; 95% CI: 1.37-2.95; relative difference: 1.44 per 1,000 patient-years; 955 CI: 0.72-2.17) and a decreased risk of hospitalization for acute kidney injury (HR: 0.66; 95% CI: 0.59-0.74; relative difference: −8.59 per 1,000 patient-years; 95% CI: −10.93 to −6.25).

Finally, in a late-breaking abstract, Avraham Karasik, MD, of Sheba Medical Center, Israel, and international colleagues presented interim EMPRISE results on the efficacy and safety of empagliflozin in routine care in Europe and East Asia. They studied 67,140 patients with type 2 diabetes who started treatment with empagliflozin or any DPP-4i identified in large databases in Israel, Finland, Germany, Spain, Sweden, South Korea, Taiwan, and Japan.

Treatment with empagliflozin compared with DPP-4is was associated with a 27% to 47% lower risk of hospitalization for heart failure, stroke, all-cause mortality, a composite outcome of hospitalization for heart failure and all-cause mortality, and a composite of myocardial infarction, stroke, and all-cause mortality. In addition, empagliflozin was associated with a 46% lower risk of acute kidney injury that required dialysis.

Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital Heart and Vascular Center, summarized the importance of the EMPRISE trial.

“We learned in the early diabetes cardiovascular outcome trials that heart failure was a big problem in diabetes patients – at least as important as their risk of heart attack, which we were previously focusing exclusively on when designing these trials,” Bhatt told BreakingMED. “This is an important ’real-world’ study that compares the SGLT2 inhibitor empagliflozin with DPP-4 inhibitors and finds an associated lower risk in all-cause mortality, hospitalization for heart failure, and acute kidney injury requiring dialysis with empagliflozin use.”

“It is very reassuring to see empagliflozin performing well in daily practice, mimicking the results seen in more carefully selected randomized clinical trial patients,” Bhatt continued. “These data nicely complement the randomized data that show that empagliflozin (versus placebo) also reduces heart failure, progression of kidney disease, and death in the EMPA-REG OUTCOME trial. The results are believable, as DPP-4 inhibitors have not been shown to improve cardiovascular outcomes in randomized trials, though they are similar to placebo with respect to cardiovascular safety.”

Benefits of SGLT2 Inhibition

Empagliflozin is an SGLT2 inhibitor that decreases glucose reabsorption in the kidneys while increasing urinary glucose excretion. The class of agents known as SGLT2 inhibitors includes empagliflozin, canagliflozin, and dapagliflozin, which are FDA-approved for the treatment of adults with type 2 diabetes in addition to diet and exercise to lower serum glucose levels. All SGLT2 inhibitors are available as single-ingredient products and in combination with other medications for diabetes such as metformin.

In January 2021, the FDA accepted the manufacturer’s supplemental new drug application for empagliflozin to reduce the risk of death or hospitalization and kidney function decline for diabetic and nondiabetic adults with chronic heart failure. Their acceptance was based on phase III data that showed an association between treatment with empagliflozin and a 25% reduction in the relative risk of the time to cardiovascular death or hospitalization due to heart failure.

“SGLT2 inhibitors have been shown to provide cardiovascular benefits in patients with diabetes in high-risk patients with established cardiovascular disease. Importantly, the SGLT2 inhibitors also provide cardiovascular benefits in diabetes patients without known cardiovascular disease. Thus, this is a class of agents that should be used more broadly in patients with type 2 diabetes, assuming they do not have contraindications,” Bhatt noted.

He added that SGLT2 inhibitors are preferred to DPP-4 inhibitors.

“Other than potential cost issues, SGLT2 inhibitors (as well as GLP1 receptor agonists) should be first-line agents for diabetes. DPP-4 inhibitors are second line agents for glycemic control. The data are overwhelming at this point. The majority of patients with type 2 diabetes should be on SGLT2 inhibitors,” Bhatt said.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Cat ID: 102

Topic ID: 74,102,730,102,3,358,446,8,12,13,187,192,669,918,925