The investigators enrolled 9340 people with type 2 diabetes, either ≥50 years of age with one or more comorbid cardiovascular condition, or ≥60 years of age with one or more cardiovascular risk factor. All were randomised in a 1:1 ratio to once-daily liraglutide 1.8 mg or placebo, in conjunction with standard care excluding other incretin-based therapies.
After a median follow-up of 3.8 years, the primary outcome, a composite of cardiovascular death, non-fatal myocardial infarction (MI) or non-fatal stroke, occurred in significantly fewer people in the liraglutide group (13.0% vs. 14.9%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79–0.97). Risk of all-cause death was also significantly reduced with liraglutide (HR, 0.85; 95% CI, 0.74–0.97).
Regarding the individual outcomes making up the composite endpoint, risk of cardiovascular death was significantly reduced (HR, 0.78; 95% CI, 0.66–0.93); however, reductions in the incidence of non-fatal MI and stroke were not significant. There were also non-significant reductions in the risk of hospitalisation for heart failure with liraglutide, which provide reassurance given previous concerns about this side effect with other incretin therapies.
The rates of adverse and serious adverse events were similar in the two arms, except for acute gallstone disease (more common with liraglutide; 3.1% vs. 1.9%) and severe hypoglycaemia (more common with placebo; 3.3% vs. 2.4%). The latter finding may be because more hypoglycaemic therapies were required to reduce HbA1c levels in the placebo group.
Liraglutide is now the second of the newer antidiabetes therapies to show beneficial effects on cardiovascular disease and death, following positive results with the sodium–glucose cotransporter 2 inhibitor empagliflozin last year. However, in the EMPA-REG OUTCOME study, empagliflozin’s benefit emerged earlier in the trial, after only 3 months, whereas in LEADER the benefits took around 18 months to become apparent. Although this difference could just reflect the different study populations or be down to chance, the authors propose that empagliflozin’s effects may be more closely related to haemodynamic changes, while liraglutide’s may have been due to the modified progression of atherosclerotic vascular disease.
This study is limited by the short follow-up (maximum 5 years) and the strict inclusion criteria of people at high cardiovascular risk, so it is impossible to know whether these results extend to other patient populations or over the longer term. Furthermore, the study was only designed to determine non-inferiority over placebo, and no adjustment for multiple comparisons was made with the secondary outcomes. Nonetheless, clinicians will be very excited to have another treatment with evidence of cardiovascular benefit for people with type 2 diabetes.
The study results can be read in full here.
