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Macrovascular Residual Risk Studies

28 July 2017
EMPA-REG OUTCOME trial: Empagliflozin and cerebrovascular events
In EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) empagliflozin was associated with a numeric albeit non-significant increase in stroke in high risk patients with type 2 diabetes mellitus. The lack of benefit on stroke may be due to modest blood pressure lowering. Zinman B, Inzucchi SE, Lachin JM et al. Empagliflozin and cerebrovascular events in patients with type
Zinman B, Inzucchi SE, Lachin JM et al. Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke 2017;48:1218-25.
Objective: To investigate the impact of empagliflozin added to standard of care on risk for stroke in patients with type 2 diabetes mellitus and high cardiovascular risk in the EMPA-REG OUTCOME trial
Study design: The EMPA-REG OUTCOME trial was a prospective double-blind randomised trial.  Patients were randomised 1:1:1 to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care therapy.
Study population: 7,020 patients with type 2 diabetes, established cardiovascular disease (CVD), and estimated glomerular filtration rate >30 mL min−1 1.73 m−2
Primary variables: The outcomes of interest in this analysis were transient ischemic attack (TIA) and stroke. Ischaemic stroke was classified post hoc according to TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment) by the neurological Clinical Events Committee.
Methods: The outcomes of interest in this analysis were transient ischemic attack (TIA) and stroke. Ischaemic stroke was classified post hoc according to TOAST criteria (Trial of Org 10172 in Acute Stroke Treatment) by the neurological Clinical Events Committee.
Main results:

Outcomes were analysed using a modified intent-to-treat approach in the treated set (patients treated with ≥1 dose of study drug), using the time to first stroke event irrespective of whether another outcome event had occurred. Data for patients who did not have an event were censored on the last day they were known to be free of the outcome.

Analyses were based on a Cox proportional hazards model, with treatment, age, sex, baseline body mass index, baseline HbA1c, baseline estimated glomerular filtration rate, and region as factors. Subgroup analyses included a subgroup factor and a treatment-by-subgroup factor interaction as additional effects. All analyses were performed at a nominal level of α=0.05 2-sided without adjustment for multiplicity.

Authors’ conclusion:

Results of the modified intention-to-treat analysis are summarised in the Table; none of these were statistically significant. Ischaemic stroke was reported in 2.7% and 3.2% of patients in the placebo and empagliflozin groups, and haemorrhagic stroke in 0.3% and 0.2% of patients in these groups, respectively.


The numeric difference in stroke between empagliflozin and placebo was primarily because of 18 patients in the empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). Sensitivity analysis based on events during treatment or within 90 days of last dose gave a hazard ratio for stroke with empagliflozin versus placebo of 1.08 (95% confidence interval, 0.81–1.45; p=0.60).


Table: Summary of results

Endpoint, n (%)

Empagliflozin (n=4687)

Placebo               (n=2333)

Hazard ratio (95% CI)        

All stroke

164 (3.5)

69 (3.0)

1.18 (0.89-1.56)

Nonfatal stroke

150 (3.2)

60 (2.6)

1.24 (0.92-1.67)

Fatal stroke

16 (0.3)

11 (0.5)

0.72 (0.33-1.55)


39 (0.8)

23 (1.0)

0.85 (0.51-1.42)


The EMPA-REG OUTCOME trial had previously shown that empagliflozin added to standard care in patients with type 2 diabetes and high cardiovascular risk, resulted in reduction in major adverse cardiovascular events. This finding was driven by reduction in cardiovascular mortality, with no significant difference between empagliflozin and placebo in risk of myocardial infarction or stroke.  However, in a modified intention-to-treat analysis (as described above), there was a numeric excess for stroke with empagliflozin versus standard of care alone, although this was not statistically significant (1).  The current analysis sought to investigate this finding.

The results show the difference in nonfatal stroke (3.2% versus 2.6% with standard of care alone, hazard ratio 1.24, 95% CI 0.92-1.67) was the main driver of this finding, with very few fatal strokes reported in each group. Moreover, sensitivity analyses showed that this finding was mainly attributed to events that occurred >90 days after the last intake of study drug (18 versus 3 on standard of care alone). As measures of the hemodynamic effects of empagliflozin, notably systolic blood pressure and haematocrit, normalised within 30 days of the last dose, the authors concluded that a causal association with empagliflozin was unlikely.

Questions therefore persist with respect to the numerical increase in (nonfatal) stroke with empagliflozin. This could not be explained by differences between regions, or patient baseline characteristics, including risk factors linked with stroke such as atrial fibrillation, smoking, previous stroke, and hypertension. Another possibility is that empagliflozin, while not preventing stroke occurrence in certain patients, made this cerebrovascular outcome less severe (ie. nonfatal instead of fatal), thereby increasing the absolute cumulative number of nonfatal stroke due to a survivor effect. The authors proposed a modest blood pressure lowering effect (-3.3 mmHg change in systolic blood pressure, from a baseline of 135 mmHg over a median treatment of 2.6 years) as another possible explanation. In contrast, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which showed a significant benefit on stroke from intensive blood pressure lowering, the mean reduction in systolic blood pressure was 14.2 mm Hg at 1 year (2).

In conclusion, the EMPA-REG OUTCOME trial did not show a benefit of empagliflozin added to standard care on the residual risk of cerebrovascular events in type 2 diabetes patients at high risk. Given the high risk of first and recurrent stroke in this patient group (3,4), it is clear that other therapeutic options are needed.


1. Zinman B, Wanner C, Lachin JM et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28.

2. ACCORD Study Group; Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85.

3. Emerging Risk Factors Collaboration; Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215–22.

4. Callahan A, Amarenco P, Goldstein LB, et al; SPARCL Investigators. Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Arch Neurol 2011;68:1245–51.

Key words stroke; type 2 diabetes; empagliflozin; residual cerebrovascular risk; blood pressure; EMPA-REG OUTCOME trial