Series: Landmark Trials in Endocrinology & Metabolism | Study #1
Category: SGLT2 Inhibitors | Design: Multicentre, double-blind, placebo-controlled RCT | n: 7,020 | Follow-up: 3.1 years (median)
📋 Summary
Authors: Zinman B et al., for the EMPA-REG OUTCOME Investigators
Journal: N Engl J Med 2015;373:2117–2128 | DOI: 10.1056/NEJMoa1504720
Patients with type 2 diabetes mellitus and established cardiovascular disease were randomly assigned to receive empagliflozin (10 mg or 25 mg once daily) or placebo in addition to standard care. The trial was event-driven, with a prespecified primary composite endpoint comprising cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Over a median follow-up of 3.1 years, the primary endpoint occurred in 490 of 4,687 participants (10.5%) in the pooled empagliflozin group and in 282 of 2,333 participants (12.1%) in the placebo group (HR 0.86; 95% CI 0.74 to 0.99; p=0.04 for superiority). Event reduction was driven predominantly by significant reductions in cardiovascular death (3.7% vs 5.9%; HR 0.62; 95% CI 0.49 to 0.77) and hospitalisation for heart failure (2.7% vs 4.1%; HR 0.65; 95% CI 0.50 to 0.85), rather than by attenuation of atherosclerotic events. All-cause mortality was reduced by 32% (HR 0.68; 95% CI 0.57 to 0.82; p<0.001). Genital infections occurred more frequently in the empagliflozin group; rates of urinary tract infection, hypoglycaemia, and diabetic ketoacidosis did not differ significantly between groups.
📊 Key Findings
| Outcome | Empagliflozin | Placebo | Effect Size |
|---|---|---|---|
| 3-point MACE (primary) | 10.5% | 12.1% | HR 0.86 (0.74–0.99) · p=0.04 |
| Cardiovascular death | 3.7% | 5.9% | HR 0.62 (0.49–0.77) · 38% RRR |
| HF hospitalisation | 2.7% | 4.1% | HR 0.65 (0.50–0.85) · 35% RRR |
| All-cause mortality | 5.7% | 8.3% | HR 0.68 (0.57–0.82) · 32% RRR |
| Nonfatal MI | 4.7% | 5.3% | HR 0.87 (0.70–1.09) · NS |
| Nonfatal stroke | 3.2% | 2.6% | HR 1.24 (0.92–1.67) · NS |
| Absolute risk reduction (MACE) | 1.6% | NNT approximately 63 over 3.1 years | |
💬 Expert Commentary
The EMPA-REG OUTCOME trial constituted a pivotal advance in cardiometabolic medicine. It was the first glucose-lowering agent to demonstrate a mortality benefit within a cardiovascular outcomes trial framework, in a regulatory landscape defined by post-market safety mandates introduced following the cardiovascular risk signal associated with rosiglitazone in 2007. The temporal pattern of the Kaplan-Meier curves merits specific attention. Separation between treatment groups was observed within weeks of randomisation, a timeline that is mechanistically inconsistent with attenuation of atherosclerotic plaque progression or coronary revascularisation effects. This early divergence directed investigative focus toward haemodynamic pathways, principally natriuresis, reductions in cardiac preload and afterload, plasma volume contraction, and potential direct myocardial metabolic effects, as the operative mechanisms underlying cardiovascular protection.
The 35% reduction in hospitalisation for heart failure was, in aggregate clinical terms, the more consequential finding. It initiated a reconceptualisation of SGLT2 inhibitors as a cardioprotective drug class rather than a glucose-lowering adjunct, and established a line of subsequent investigation that extended the indication to patients without diabetes entirely. The absolute risk reduction for MACE of 1.6%, corresponding to an NNT of approximately 63 over 3.1 years, contextualises the relative risk data within a high-risk trial population and should inform individualised prescribing decisions. The failure of nonfatal MI and nonfatal stroke to reach individual statistical significance supports the conclusion that the predominant mechanism of benefit is myocardial and haemodynamic rather than anti-atherosclerotic, a distinction relevant to patient selection and comparative effectiveness with other cardioprotective drug classes.
Limitations: The trial enrolled exclusively patients with established cardiovascular disease, restricting generalisability to primary prevention or lower-risk type 2 diabetes populations. The study cohort was predominantly of White European and North American ethnicity. Active doses of 10 mg and 25 mg were pooled for the primary analysis, precluding dose-specific inference. No active cardiovascular comparator was included in the trial design. The study was industry-sponsored by Boehringer Ingelheim and Eli Lilly.
🔑 BOTTOM LINE
Empagliflozin reduced cardiovascular death and hospitalisation for heart failure in patients with type 2 diabetes and established cardiovascular disease with a magnitude and temporal pattern that established haemodynamic cardioprotection, rather than glycaemic modification, as the central mechanism of benefit. This trial permanently repositioned SGLT2 inhibitors within cardiovascular risk reduction frameworks and provided the foundational evidence for subsequent renal and heart failure outcome trials across the drug class.
⭐ Clinical Impact Rating: ●●●●● Practice-defining
Next in the series: Study #2 CANVAS Programme: Canagliflozin and Cardiovascular Events in Type 2 Diabetes
