Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME^®trial

Abstract

AimsWe previously reported that in the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure.Methods and resultsPatients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin [265/4687 patients (5.7%)] than with placebo [198/2333 patients (8.5%)] [hazard ratio, HR: 0.66 (95% confidence interval: 0.55–0.79); P < 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure [2.8 vs. 4.5%; HR: 0.61 (0.47–0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization [36.8 vs. 39.6%; HR: 0.89 (0.82–0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo.ConclusionIn patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure.

Cardiovascular safety of oral antidiabetic therapy in type 2 diabetes mellitus- review article

“…78 In the liraglutide effect and action in diabetes: Evaluation Of Cardiovascular Outcome Results (LEADER) trial, which randomized 9340 T2DM patients with high cardiovascular risk, liraglutide reduced the primary composite endpoint of cardiovascular death, non-fatal MI or non-fatal stroke compared to placebo after a median follow-up of 3years. 79,80 Although not currently FDA approved, semaglutide, a once-weekly GLP-1 agonist, was non-inferior to placebo after 26 months follow up among 3297 patients with T2DM in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) with regards to the primary composite endpoint of cardiovascular death, non-fatal MI and nonfatal stroke. 81 Notably, majority of the trial patients had established cardiovascular disease, stage 3 or higher chronic kidney disease, or both at baseline.…”

“…75,79,81,82 Inhibition of SGLT-2 lowers blood glucose by promoting renal glucose excretion, which is independent of β-cell function and thus carries a low risk for hypoglycemia. 77,78,80,82 Currently, 3 agents are approved in the United States and Europe: dapagliflozin, canagliflozin, and empagliflozin.…”

“…SGLT-2 inhibitors reduce HbA1c by 0.5-0.7% compared with placebo. [75][76][77][78][79][80][81][82] and promotes weight loss of 2-3 kg over 12 weeks. It has a modest beneficial effect on the lipid profile through an increase in high density lipoprotein cholesterol and decrease in triglycerides.…”

“…[79][80][81][82] Further analysis showed a 34% relative risk reduction of a composite of heart failure hospitalization or cardiovascular death with empagliflozin. Driven mainly by these results, a metaanalysis of data from regulatory submissions and published trials suggested net protection of SGLT-2 inhibitors against cardiovascular outcomes and death.…”

GLP-1 receptor agonists and heart failure in diabetes

“…Recently, some concerns have also been raised with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin, following the publication of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) -Thrombolysis in Myocardial Infarction (TIMI) 53 trial [7], a finding that casts some suspicion on the entire incretin-based pharmacological class [8][9][10]. In contrast, a marked, significant reduction in hospitalizations for HF has been reported with the sodium -glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) [11,12]. Because hospital admission for HF is a common and serious factor associated with a higher risk of death, HF is a cardiovascular outcome that can no longer be ignored in diabetic patients, especially when choosing a glucose-lowering agent [13].…”