Efficacy and safety outcomes of dulaglutide by baseline HbA1c: A post hoc analysis of the REWIND trial

Abstract

Aim: To assess cardiovascular, glycaemic, weight and safety outcomes of long-term treatment with dulaglutide 1.5 mg compared with placebo in patients with a baseline HbA1c of less than 7% versus 7% or higher.

Materials and methods: Intention-to-treat analyses were performed on REWIND participants with a baseline HbA1c measurement, using Cox proportional hazards regression and mixed model for repeated measures. Subgroup analyses with factors for baseline HbA1c categories and their interaction with treatment group, as well as analyses within the HbA1c subgroups, were conducted. Additionally, sensitivity analyses were performed for baseline HbA1c subgroups of 6.5% or less and more than 6.5%.

Results: Of the 9876 eligible participants, 3921 and 5955 had a baseline HbA1c of less than 7% and 7% or higher, respectively. Mean baseline HbA1c was 6.3% and 8.0% and the mean duration of diabetes was 9.0 and 11.6 years in the respective subgroups. The less than 7% subgroup was slightly older and less frequently insulin-treated. There was no evidence of a differential dulaglutide treatment effect on body mass index (BMI) reduction, cardiovascular or safety outcomes of interest between the baseline HbA1c subgroups. Treatment-by-baseline HbA1c group interaction was significant for HbA1c change from baseline (P < .001), with a greater reduction in the subgroup with higher baseline HbA1c values. Sensitivity analyses by baseline HbA1c subgroups of 6.5% or less and more than 6.5% showed similar results.

Conclusions: The reduced incidence of cardiovascular events, and the reduction in BMI in participants treated with once-weekly dulaglutide, were independent of the baseline HbA1c level. Conversely, participants with a higher baseline HbA1c level had greater reductions in HbA1c. Dulaglutide has a positive benefit-risk profile and can be considered in patients with comparatively well-controlled HbA1c levels seeking optimal metabolic control and cardiovascular benefits.

Trial registration: ClinicalTrials.gov NCT01394952.

Keywords: cardiovascular disease; clinical trial; dulaglutide; glycaemic control; incretin therapy; type 2 diabetes.

FIGURE 1

Mean HbA1c and body mass index (BMI) over 60 months of treatment by randomized treatment and higher or lower HbA1c group. Changes in A, HbA1c, and B, BMI, show that HbA1c values were significantly lower and BMI reduction was significantly greater in the baseline HbA1c <7% and ≥7% subgroups treated with dulaglutide (DU). Treatment‐by‐baseline HbA1c group interaction was significant for change from baseline in HbA1c (P < .001). Treatment‐by‐baseline HbA1c group interaction was not significant for change from baseline in BMI (P = .345). BL, baseline; LSM, least squares mean

FIGURE 2

Hazard ratios (HRs) for cardiovascular events by HbA1c subgroups. A, There was no evidence of a differential treatment effect between the baseline HbA1c subgroups in major adverse cardiovascular events‐3 (MACE‐3), non‐fatal myocardial infarction events, non‐fatal stroke events, cardiovascular‐related deaths, all‐cause deaths, and hospitalizations because of heart failure events by overall patient groups, and baseline HbA1c <7% and ≥7% subgroups. Number of overall patients: dulaglutide = 4949; placebo = 4952. Number of patients with baseline HbA1c < 7%: dulaglutide = 1972; placebo = 1949. Number of patients with baseline HbA1c ≥ 7%: dulaglutide = 2967; placebo = 2988. The overall population also contains 25 patients that could not be included in any HbA1c subgroup because of missing HbA1c at baseline. ^aNumber of patients per 100 person‐years. ^bIncludes deaths of unknown causes. B, Treatment effect of dulaglutide (N = 4939) compared with placebo (N = 4937) as a function of baseline HbA1c (continuous, [%]) for the primary outcome, MACE‐3. The solid black line represents the estimated HR of the treatment effect. The grey shaded area represents the 95% CI around the treatment effects. The dotted horizontal line represents an HR of 1 (i.e. no difference between randomized groups). Estimated HR and 95% CI values are displayed for baseline HbA1c between the observed 10th and 90th percentiles

FIGURE 3

Hazard ratios (HRs) for safety outcomes of interest by HbA1c subgroups. Analysis of discontinuations for any reason, discontinuations because of adverse events, severe hypoglycaemia events, serious renal or urinary events, and serious gastrointestinal events by overall patients, and baseline HbA1c <7% and ≥7% subgroups. Number of overall patients: dulaglutide = 4949; placebo = 4952. Number of patients with baseline HbA1c <7%: dulaglutide = 1972; placebo = 1949. Number of patients with baseline HbA1c ≥7%: dulaglutide = 2967; placebo = 2988. The overall population also contains 25 patients that could not be included in any HbA1c subgroup because of missing HbA1c at baseline. ^aNumber of patients per 100 person‐years