New England Journal of Medicine November 26, 2015

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)

Bernard Zinman, Christoph Wanner, John M. Lachin, et al. (EMPA-REG OUTCOME Investigators)

Bottom Line

In patients with type 2 diabetes and established cardiovascular disease, the SGLT2 inhibitor empagliflozin significantly reduced the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, primarily driven by a marked reduction in cardiovascular mortality.

Key Findings

1. The primary composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 10.5% of the pooled empagliflozin group compared to 12.1% of the placebo group (HR 0.86; 95% CI, 0.74 to 0.99; P=0.04 for superiority).

2. Empagliflozin treatment resulted in a striking 38% relative risk reduction in cardiovascular death, which occurred in 3.7% of treated patients versus 5.9% in the placebo group (HR 0.62; 95% CI, 0.49 to 0.77; P<0.001).

3. All-cause mortality was significantly lower in the empagliflozin group (5.7%) compared to the placebo group (8.3%), translating to a 32% relative risk reduction (HR 0.68; 95% CI, 0.57 to 0.82; P<0.001).

4. Hospitalization for heart failure was significantly reduced, occurring in 2.7% of the empagliflozin group versus 4.1% of the placebo group (HR 0.65; 95% CI, 0.50 to 0.85; P=0.002).

5. There were no significant differences between the empagliflozin and placebo groups in the rates of nonfatal myocardial infarction (4.5% vs. 5.2%; HR 0.87) or nonfatal stroke (3.5% vs. 3.0%; HR 1.18).

Study Design

Design

RCT

Double-Blind

Sample

7,020

Patients

Duration

3.1 yr

Median

Setting

Multicenter, global

Population Adults with type 2 diabetes mellitus (HbA1c 7.0-10.0%) and established cardiovascular disease

Intervention Empagliflozin (10 mg or 25 mg) once daily in addition to standard care

Comparator Matching placebo once daily in addition to standard care

Outcome Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-point MACE)

Study Limitations

• The trial exclusively enrolled high-risk patients with established cardiovascular disease, limiting the generalizability of the findings to lower-risk populations or those with early-stage type 2 diabetes.

• The study was not powered to discern efficacy differences between the 10 mg and 25 mg doses of empagliflozin, which were consequently pooled for the primary analysis.

• Women and non-White patients were relatively underrepresented in the study cohort.

• The exact physiological mechanisms driving the rapid cardiovascular benefits remained speculative, as the trial was not designed to definitively isolate hemodynamic, metabolic, or direct myocardial effects.

Clinical Significance

EMPA-REG OUTCOME fundamentally revolutionized the management of type 2 diabetes. By demonstrating that empagliflozin could substantially reduce cardiovascular mortality and heart failure hospitalizations, it became the first trial to prove that an antihyperglycemic agent could confer profound cardiovascular benefits. This catalyzed a global paradigm shift in clinical guidelines, elevating SGLT2 inhibitors to foundational, disease-modifying therapies for patients with high cardiovascular or heart failure risk, independent of glycemic targets.

Historical Context

Following the 2008 controversy surrounding rosiglitazone and its potential cardiovascular risks, the FDA mandated that all new diabetes medications undergo rigorous cardiovascular outcome trials (CVOTs) to prove safety. Early CVOTs for DPP-4 inhibitors established non-inferiority but failed to show cardiovascular benefit. In 2015, EMPA-REG OUTCOME became the landmark breakthrough of this modern regulatory era, shattering expectations by demonstrating sweeping superiority in reducing cardiovascular events and ushering in a new era of cardiorenal risk reduction.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of SGLT2 inhibitors like empagliflozin explain both their glucose-lowering effect and their notable cardiovascular benefits seen in the EMPA-REG OUTCOME trial?

Key Response

This question tests foundational understanding of the sodium-glucose cotransporter 2 in the proximal tubule. Inhibition leads to glycosuria and osmotic diuresis, which lowers glucose but also reduces preload, lowers blood pressure, and modulates tubuloglomerular feedback, explaining the early cardiovascular benefits.

Resident

Based on the EMPA-REG OUTCOME inclusion criteria and the known adverse effect profile of SGLT2 inhibitors, which patients in your primary care clinic are ideal candidates for empagliflozin, and what specific risks must you counsel them about?

Key Response

Connects trial population (T2DM with established ASCVD) to practical prescribing. Residents must identify appropriate high-risk patients while knowing to monitor for euglycemic diabetic ketoacidosis, severe mycotic genital infections, and volume depletion risks.

Fellow

The primary MACE reduction in EMPA-REG OUTCOME was driven overwhelmingly by a reduction in CV death with early separation of the Kaplan-Meier curves, rather than a reduction in atherothrombotic events like MI or stroke. What mechanistic hypotheses explain this early mortality benefit compared to GLP-1 receptor agonists?

Key Response

Explores the nuanced differences in cardiovascular outcome trials. The early benefit suggests hemodynamic effects like reduced preload and afterload, shift to myocardial ketone metabolism, and diuresis, contrasting with the slower, anti-atherosclerotic plaque-stabilizing effects typically seen with GLP-1 RAs.

Attending

EMPA-REG OUTCOME marked a paradigm shift from a 'glucocentric' approach to a 'cardio-renal risk reduction' approach in diabetes management. How does this trial fundamentally change our approach to polypharmacy in older patients with T2DM, and how do we prioritize disease-modifying therapies over pure glycemic control?

Key Response

Emphasizes the historical context of FDA-mandated CV safety trials and how this trial transformed SGLT2 inhibitors into foundational cardiovascular drugs, altering treatment algorithms to prioritize mortality and heart failure benefits regardless of A1c levels.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The EMPA-REG OUTCOME trial was designed as a non-inferiority safety trial but achieved superiority. Methodologically, how does transitioning from non-inferiority to superiority testing within a hierarchical closed testing procedure impact the Type I error rate, and what are the limitations of interpreting secondary endpoints in this context?

Key Response

Critiques the statistical framework of hierarchical gatekeeping used in cardiovascular outcome trials. Researchers must understand how proving efficacy in a safety trial handles multiplicity, alpha-spending, and the rigorous boundaries required to declare statistical significance for subsequent endpoints.

Journal Editor

Nearly 25 percent of patients in EMPA-REG OUTCOME discontinued the study drug prematurely, yet the trial utilized an intention-to-treat analysis. As an editor, how might this high dropout rate introduce bias, and what specific sensitivity or on-treatment analyses would you demand to ensure the robustness of the mortality benefit?

Key Response

Targets rigorous critical appraisal. High discontinuation rates in long-term trials pose threats to validity; an editor must evaluate how missing data and non-adherence affect the intention-to-treat estimator and require robust missing-data imputation models to verify the results.

Guideline Committee

Following the EMPA-REG OUTCOME results, how should the ADA Standards of Care and ACC/AHA guidelines be updated regarding the sequencing of glucose-lowering agents in patients with T2DM and established ASCVD? Should SGLT2 inhibitors be recommended independently of baseline HbA1c or prior metformin use?

Key Response

Relates directly to guideline evolution. Post-EMPA-REG, ADA and EASD guidelines shifted to a Class 1 recommendation for SGLT2 inhibitors in T2DM patients with ASCVD, heart failure, or CKD, notably recommending their use independently of A1c targets or metformin sequencing, fundamentally rewriting treatment algorithms.

Clinical Landscape

Noteworthy Related Trials

2017

CANVAS Program

n = 10,142 · NEJM

Tested

Canagliflozin 100 mg or 300 mg daily

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Canagliflozin significantly reduced the risk of cardiovascular events but was associated with an increased risk of lower-limb amputations.

2019

DECLARE-TIMI 58

n = 17,160 · NEJM

Tested

Dapagliflozin 10 mg daily

Population

T2DM patients with established CV disease or multiple risk factors

Comparator

Placebo

Endpoint

3-point MACE and CV death or hospitalization for heart failure

Key result: Dapagliflozin resulted in a lower rate of cardiovascular death or hospitalization for heart failure, primarily driven by reduced heart failure hospitalizations.

2019

CREDENCE Trial

n = 4,401 · NEJM

Tested

Canagliflozin 100 mg daily

Population

T2DM patients with albuminuric chronic kidney disease

Comparator

Placebo

Endpoint

Composite of ESKD, doubling of serum creatinine, or renal/CV death

Key result: Canagliflozin significantly reduced the risk of kidney failure and cardiovascular events in patients with type 2 diabetes and kidney disease.

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