Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study)

Abstract

Background: Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).

Methods: A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups.

Results: We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]).

Conclusions: This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

Keywords: cardiovascular diseases; diabetes mellitus; glucose; liraglutide.

Figure 1.. Kaplan-Meier curves for each of the CV outcomes among the GRADE treatment groups.

Cumulative incidence of composite cardiovascular outcomes (panel A) and of their components (panel B). The shaded bar along the x-axis of each figure indicates the number of participants available for analyses. The p-values are from the log-rank tests with no adjustment for multiple comparisons. MI = myocardial infarction; CV = cardiovascular; Revasc = revascularization; HHF = hospitalization for heart failure; UA = unstable angina; MACE = major adverse cardiovascular events; MACE-3 = a composite of MI, stroke (CVA), and CV death. P-values are not adjusted for multiple comparisons

Figure 2.. Pairwise comparison of MACE-6 recurrent event analysis.

This figure summarizes the 6 pairwise comparisons among the 4 treatment groups (glargine, glimepiride, liraglutide, and sitagliptin) for ALL MACE-6 events using solid and dashed lines to denote significance. A solid line between any 2 treatment groups means that the 2 groups have significantly different event rates for ALL MACE-6 events: a dashed line between any 2 treatment groups means that the 2 groups do not differ significantly in their total MACE-6 event rates. The p-value for each pairwise comparison is provided in the center of the solid or dashed line between the 2 relevant treatment groups. Of note, after adjustment for multiple comparisons using the Holm procedure for the 4 treatment groups (6 pairwise comparisons), liraglutide has a lower risk than either glimepiride (HR: 1.63) or sitagliptin (HR: 1.77); however, liraglutide’s lower risk estimate compared to glargine (HR: 1.51) is no longer significant (p-value = 0.063). The remaining pairwise comparisons are not significant. The rate ratios (RR) denote the event rate of ALL MACE-6 events in the glargine, glimepiride, and sitagliptin groups, respectively, relative to liraglutide (the reference group) and arise from the proportional rate model as described in the text. MACE = major adverse cardiovascular events; MACE-6 = a composite of myocardial infarction, stroke, CV death, unstable angina requiring hospitalization, coronary revascularization and hospitalization for heart failure; ALL MACE-6 = all first and recurrent MACE-6.

Figure 3.. Mean number of all MACE-6 events (first and recurrent) per participant, by treatment group.

Mean number of ALL MACE-6 events (first and recurrent) by treatment group up to 5 years post-randomization. The liraglutide treatment group had the lowest mean number of ALL MACE-6 events per participant throughout the 5 years. The shaded areas represent 95% confidence bands for mean participant event estimates by treatment group.