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4 January 2021
Empagliflozin reduced the total burden of cardiovascular complications in type 2 diabetes patients with cardiovascular disease
This latest report from the EMPA-REG OUTCOME trial showed continued aggregation of benefit beyond first cardiovascular events with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin on top of the current standard of care.
McGuire DK, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on first and recurrent clinical events in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a secondary analysis of the EMPA-REG OUTCOME trial. Lancet Diabetes Endocrinol 2020;8:949-59.
Objective: To investigate the effect of empagliflozin on total cardiovascular events and admissions to hospital in the EMPA-REG OUTCOME trial.
Study design: This was a prespecified analysis of the EMPA-REG OUTCOME trial, a randomised, double-blind, non-inferiority trial conducted between August 2010 and April 2015.
Study population: 7020 patients aged ≥18 years with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) allocated to empagliflozin 10 mg (n=2345), empagliflozin 25 mg (n=2342), or placebo (n=2333).
Main Study variables:

•Primary: major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal stroke, or non-fatal myocardial infarction

•Additional efficacy endpoints: fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, and admission to hospital for heart failure.

Methods: The total events analysis (first plus recurrent events) compared the effects of empagliflozin (pooled doses) and placebo on the total burden of ASCVD events, using statistical models that preserve randomisation and account for correlation of recurrent events.
Main results:

Over a median follow-up of 3.2 years in the pooled empagliflozin group and 3.1 years in the placebo group, 772 (11%) of the total study population had a MACE, of whom 129 (16.7%) had a recurrent MACE. Treatment with empagliflozin reduced total MACE to a greater extent than the risk reduction seen for first events; the rate ratio was 0.78, 95% confidence interval (CI) 0.67–0.91, for total events versus 0.86, 95%CI 0.74–0.99, for first events. Additionally, treatment with empagliflozin reduced total admissions to hospital for heart failure by 42% versus 35% for first admissions (rate ratio: 0·58, 95%CI 0.42–0.81, versus 0.65, 95%CI 0.50–0.85). 

Importantly, treatment with empagliflozin prevented twice as many total MACE per 1000 patient-years (12.9, 95% CI 3.74–22.02) compared with first events (6.5, 95% CI 0.37–12.59), as well as twice as many admissions to hospital for heart failure (9.7 total events versus vs 5.1 first events per 1000 patient-years). 

Authors’ conclusion: Empagliflozin reduced the total burden of cardiovascular complications and all-cause admission to hospital in patients with type 2 diabetes and ASCVD.


Cardiovascular outcomes studies primarily focus on prevention of first events. From the perspective of healthcare systems, payers and policy makers, however, the total cardiovascular disease burden is more relevant, given that societal costs increase with recurrent events and progression of cardiovascular complications. For example, in the REACH (Reduction of Atherothrombosis for Continued Health) registry, about one in five patients with diabetes and ASCVD experienced a MACE (either first or recurrent) over 4 years (1), similar to data reported in this analysis of the EMPA-REG OUTCOME study. The cost associated with treating these patients is substantial, with a large proportion attributable to inpatient stay. Therefore, a total events analysis which captures both first and recurrent events provides important information for guidelines and policy makers. 

This latest report from the EMPA-REG OUTCOME trial showed that the benefit of empagliflozin on total MACE was significantly greater than for first events (2), with prevention of twice as many MACE, as well as twice as many hospitalisations for heart failure. This suggests that treatment with empagliflozin impacts the trajectory of ASCVD and heart failure in type 2 diabetes. These findings are consistent with those reported from the LEADER study (3), in which post hoc analyses showed that treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduced the overall burden of cardiovascular events compared with placebo among high-risk patients with type 2 diabetes. These findings will undoubtedly impact future iterations of guidelines for the management of patients with type 2 diabetes (4). 

References 1. Cavender MA, Steg PG, Smith SC Jr, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at 4 years from the reduction of atherothrombosis for continued health (REACH) registry. Circulation 2015;132:923‐31. 
2. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373: 2117–28. 
3. Verma S, Bain SC, Buse JB, et al. Occurence of first and recurrent major adverse cardiovascular events with liraglutide treatment among patients with type 2 diabetes and high risk of cardiovascular events: a post hoc analysis of a randomized clinical trial. JAMA Cardiol 2019;4:1214-20.
4. Aroda VR, Sabatine MS. EMPA-REG OUTCOME and beyond: the long game of cardiovascular risk reduction. Lancet Diabetes Endocrinol 2020;8:932-3.
Key words empagliflozin, type 2 diabetes; total cardiovascular disease burden