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Macrovascular Residual Risk Studies

6 November 2015
Landmark positive results in EMPA-REG OUTCOME study with empagliflozin, an inhibitor of sodium–glucose cotransporter 2
Treatment with empagliflozin, in addition to standard of care, significantly reduced major cardiovascular events and death from any cause in patients with type 2 diabetes at high risk for cardiovascular events.
Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; DOI: 10.1056/NEJMoa1504720
Objective: To compare the effects of empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, in addition to standard care, versus placebo (standard care alone), on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events.
Study design: Randomized, double-blind, placebo-controlled trial. Eligible patients underwent a 2-week, open-label, placebo run-in period in which background glucose-lowering therapy was unchanged, before randomisation to once-daily empagliflozin (10 mg or 25 mg once daily) or placebo (1:1:1) against a background of standard care. Randomisation was performed using a computer-generated random-sequence and interactive voice- and Web-response system and was stratified according to glycated haemoglobin (HbA1c) at screening (<8.5% or ≥8.5%), body mass index at randomisation (<30 or ≥30 kg/m2), renal function at screening (estimated glomerular filtration rate, eGFR, 30 to 59, 60 to 89, or ≥90 ml/min/1.73 m2), and geographic region.
Study population:

Type 2 diabetes patients with established cardiovascular risk receiving standard care. Patients either had received no glucose-lowering agents for at least 12 weeks before randomisation and had an HbA1c between 7.0% and 9.0%, or had received stable glucose-lowering therapy for at least 12 weeks before randomisation and had an HbA1c between 7.0% and 10.0%.
7,028 patients were randomised, of whom 7,020 were treated and included in the primary analysis.

Primary efficacity measures: A composite of death from cardiovascular causes, nonfatal myocardial infarction (MI, excluding silent MI), or nonfatal stroke.
Secondary efficacity measures:

The key secondary outcome was a composite of the primary outcome
plus hospitalisation for unstable angina.


The primary hypothesis was noninferiority for the primary outcome with empagliflozin (pooled doses of 10 mg and 25 mg) versus placebo with a margin of 1.3 for the hazard ratio. A 4-step hierarchical-testing strategy was used: noninferiority for the primary outcome, noninferiority for the key secondary outcome, superiority for the primary outcome, and superiority for the key secondary outcome. Noninferiority for the primary outcome was established if the upper limit of the 2-sided 95.02% confidence interval was less than 1.3. For superiority, a 2-sided p value of £0.0498 was indicative of statistical significance. Analyses were based on a Cox proportional-hazards model, with study group, age, sex, baseline body-mass index, baseline HbA1c level, baseline eGFR, and geographic region as factors.

The primary analysis used a modified intention-to-treat approach including patients who had received at least one dose of study drug.

Main results:
  • Over a median follow-up was 3.1 years, treatment with empagliflozin significantly reduced the primary outcome, and was also associated with significant reduction in both all-cause and cardiovascular mortality (Table 1). There was a consistent benefit of empagliflozin versus placebo on death from cardiovascular causes across all subgroups.
  • This benefit on survival was evident from 3 months.
  • In terms of numbers needed to treat, 39 patients would need to be treated with empagliflozin during a 3-year period to prevent one death.
  • Treatment with empagliflozin did not significantly reduce the key secondary outcome.
  • For the other individual outcomes, hospitalization for heart failure was decreased with empagliflozin (by 35%, p=0.002). There was no significant treatment effect for the other individual outcomes (other than death).
  • The rates of any adverse event, serious adverse events, and adverse events leading to the discontinuation rates were similar with empagliflozin or placebo. Among patients receiving empagliflozin, there was an increased rate of genital infection and urosepsis, but no increase in other adverse events.

Table 1. Primary and secondary outcomes






Hazard ratio (95% CI)







Primary, n (%)

282 (12.1)

490 (10.5)

0.86 (0.74–0.99)

















Key secondary, n (%)

333 (14.3)

599 (12.8)

0.89 (0.78–1.01)

















Death, n (%)





From any cause

194 (8.3)

269 (5.7)

0.68 (0.57–0.82)


Cardiovascular death

137 (5.9)

172 (3.7)

0.62 (0.49–0.77)


* One-sided p- values are shown for tests of noninferiority, and two-sided p-values are for tests of superiority

Authors’ conclusion: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.


Much of the focus from the R3i perspective has been on lipid-related residual cardiovascular risk. However, the results of the EMPA-REG OUTCOME study highlight the importance of non-lipid risk factors as contributors to residual cardiovascular risk. This study showed that the addition of empagliflozin, a selective SGLT2 inhibitor, to standard of care, significantly reduced major cardiovascular events. The key driver of this benefit was reduction in cardiovascular mortality, with no significant benefit on other components of the primary outcome.  It is important to note that the patient population was well treated for other cardiovascular risk factors, including blood pressure and dyslipidaemia, with comparable use of renin–angiotensin–aldosterone system inhibitors, statins, and acetylsalicylic acid.  However, many patients did not attain HbA1c targets (mean at week 206, 7.81% with empagliflozin versus 8.16% with placebo).

The key question posed by these findings is what is the mechanism(s) underlying the benefit of empagliflozin on cardiovascular death? Given that the trial does not permit direct insights, a range of possible mechanisms have been proposed, including a possible osmotic-diuretic effect of empagliflozin. Indeed, this is an ongoing debate in the clinical community and merits further investigation. Among questions raised by the trial is whether similar benefits would be observed in a primary prevention type 2 diabetes population, in pre-diabetic populations, or in non-diabetic patients with established CVD, whether this is a class effect of all SGLT2 inhibitors, and whether the findings merit a change in diabetes guidelines.

Finally, a key question is whether treatment with empagliflozin would impact renal outcomes; analyses have yet to be reported. Indeed, the possibility that the SGLT2 inhibitors have renoprotective effects has been previously suggested by mechanistic studies (1, 2), and is the focus of two ongoing trials, CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) and CANVAS-R (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus) (3,4). If favourable, empagliflozin may offer potential not only for reducing macrovascular residual risk, but also microvascular residual risk in type 2 diabetes patients with established cardiovascular disease.


1. Kojima N, Williams JM, Slaughter TN et al. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats. Physiol Rep 2015;3(7). pii: e12436.

2. Kojima N, Williams JM, Takahashi T et al. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther 2013;345:464-72.

3. Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE). Identifier: NCT02065791.

4. A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R). Identifier: NCT01989754
Key words type 2 diabetes; cardiovascular risk; all-cause mortality, cardiovascular mortality; empagliflozin