EMPA-REG OUTCOME Trial: Reducing Cardiovascular Risk For T2D Patients

The results of EMPA-REG OUTCOME Trial assess the role of empagliflozin in patients with type 2 diabetes and atherosclerotic cardiovascular disease.

Patients with both type 2 diabetes and ASCVD are at high risk of cardiovascular events, even with proper management. Previous studies have focused on sodium-glucose cotransporter 2 (SGLT2) inhibitors’ cardiovascular efficacy; however, previous trials have not seen a reduction of cardiovascular mortality until the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes (EMPA-REG OUTCOME). While this study focused on patients with type 2 diabetes and ASCVD, what about cardiovascular benefits in patients with ASCVD risk factors, but no proven ASCVD?

The study used data from the EMPA-REG OUTCOME trial to conduct a prospective study to determine the range of predicted and observed cardiovascular risk in patients with both type 2 diabetes (HbA1c 7-10%) and ASCVD. The authors also wanted to examine the effects of empagliflozin on cardiovascular outcomes and mortality across the range of cardiovascular risk at baseline. In the EMPA-REG OUTCOME, 7020 patients were randomized into 1 of 3 groups to receive either empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily with their standard care. In the current study, outcomes measured were risks of cardiovascular death, all-cause mortality, 3-point major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), and the composite of HHF or cardiovascular death.

Multivariable Cox proportional hazards regression analyses were used to compare the differences in risk for the different doses of empagliflozin combined versus placebo. The main analysis model was used in two instances, the first in subgroup analyses by history of MI or stroke at baseline, and the second, subgroup analyses by the Thrombolysis In Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P) at baseline. Patients were in 1 of 4 groups based on their 10-point TRS 2°P risk scores of < 2 points (low risk), 3 points (intermediate risk), 4 points (high risk), and > 5 points (highest risk).

Of the patients in the study, 65% in both empagliflozin intervention groups and placebo had a prior MI or stroke. The other 35% had coronary artery disease and peripheral artery disease without a prior MI and stroke. In the placebo group, 7% of patients with a prior MI or stroke died of cardiovascular death, versus 3.7% in patients without prior MI or stroke. Patients with, versus without, prior MI or stroke also had a higher proportion of all-cause mortality, 3-point MACE, and HF outcomes. In patients taking empagliflozin, the reductions in all outcomes were consistent in patients with and without a prior MI or stroke (P > 0.05). Randomized group-by-subgroup interaction tests showed similar results from the effects of empagliflozin versus placebo in the subgroups by prior MI and prior stroke (P > 0.05).

When stratified by TRS 2°P at baseline, 12% of patients were at low cardiovascular risk, 40% at intermediate, 30% at high, and 18% with highest risk. Similar proportions were seen between empagliflozin versus placebo. In the placebo group 2.2% to 11.2% of patients died due to cardiovascular death and those with HHF ranged from 1.1% to 10%. Patients with greater TRS 2°P at baseline had an increased proportion of patients with all-cause mortality and 3-point MACE. As seen previously, the reduction of outcomes with empagliflozin versus placebo was consistent across subgroups by baseline TRS 2°P (P > 0.05).

The authors concluded that empagliflozin reduces mortality and HHF across a range of cardiovascular risk. Benefits were seen no matter the degree of cardiovascular risk in patients with type 2 diabetes and prevalent ASCVD. Applying this study to previous studies focusing on empagliflozin, they believe patients with type 2 diabetes and cardiovascular risk would benefit by adding it to their treatment regimen. Future trials may assess the overall class of SGLT2 inhibitors to determine if any are superior to the others in terms of reducing cardiovascular outcomes.

Practice Pearls:

• Patients with type 2 diabetes and ASCVD are at high risk of cardiovascular events.
• Empagliflozin showed its ability to reduce mortality and HHF in patients across the range of cardiovascular risk.
•  In patients irrespective of prior history of MI or stroke, patients might benefit adding empagliflozin to their treatment regimen.

Fitchett, David, et al. Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation. 2019 March 12.

Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate

See our clinical presentation for more on the EMPA-REG OUTCOME Trial.