Neoplasms Reported With Liraglutide or Placebo in People With Type 2 Diabetes: Results From the LEADER Randomized Trial

Abstract

Objective: This study explored neoplasm risk with liraglutide versus placebo in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) cohort.

Research design and methods: LEADER (NCT01179048) was an international, phase 3b, randomized, double-blind, controlled trial. Participants aged ≥50 years with type 2 diabetes and high cardiovascular risk were assigned 1:1 to receive liraglutide (≤1.8 mg daily; n = 4,668) or placebo (n = 4,672) in addition to standard care and monitored for 3.5-5 years (median follow-up 3.8 years). The occurrence of neoplasms was a prespecified, exploratory secondary end point. Post hoc analyses of the time to the first confirmed neoplasms were conducted using a Cox regression model.

Results: Neoplasm was confirmed in 10.1% of patients with liraglutide versus 9.0% with placebo (hazard ratio [HR] 1.12 [95% CI 0.99; 1.28]). The HR (95% CI) for liraglutide versus placebo was 1.06 (0.90; 1.25) for malignant neoplasms and 1.16 (0.93; 1.44) for benign neoplasms. Sensitivity analyses excluding neoplasms occurring <1 year or <2 years after randomization and analyses by sex provided similar results. In our main analyses, the 95% CI for the HR included one for all malignant neoplasms evaluated (including pancreatic and thyroid neoplasms) except for prostate neoplasms, which occurred in fewer liraglutide-treated patients.

Conclusions: LEADER was not primarily designed to assess neoplasm risk. Firm conclusions cannot be made regarding numeric imbalances observed for individual neoplasm types (e.g., pancreatic cancer) that occurred infrequently. LEADER data do, however, exclude a major increase in the risk of total malignant neoplasms with liraglutide versus placebo. Additional studies are needed to assess longer-term exposure.

© 2018 by the American Diabetes Association.

Figures

Figure 1

Frequency of all confirmed neoplasms, malignant neoplasms, benign neoplasms, and neoplasms of interest. A: Main analysis. B and C: Events occurring later than 1 year (B) and later than 2 years (C) after randomization (sensitivity analysis) (11). Data presented in this table refer to the full analysis set (FAS). HRs are derived from a Cox proportional hazard regression model adjusted for treatment. Firth correction was used for malignant pancreatic neoplasms occurring later than 2 years after randomization (C). Proportions for breast neoplasms are calculated based on the number of female participants. Proportions for prostate neoplasms are calculated based on the number of male participants. Reprinted from Marso et al. (11) with permission from the Massachusetts Medical Society. © 2016 Massachusetts Medical Society.

Figure 2

Cumulative incidence plots for confirmed neoplasms. A: Confirmed neoplasm index events. B and C: Confirmed neoplasm index events occurring later than 1 year (B) and later than 2 years (C) after randomization (sensitivity analysis). D: Confirmed malignant neoplasm index events. E and F: Confirmed malignant neoplasm index events occurring later than 1 year (E) and later than 2 years (F) after randomization (sensitivity analysis). G: Confirmed benign neoplasm index events. H and I: Confirmed benign neoplasm index events occurring later than 1 year (H) and later than 2 years (I) after randomization (sensitivity analysis). Cumulative incidence was estimated using the Aalen-Johansen method with death as a competing risk. A cumulative incidence probability of 0.1 is equivalent to 10%. HRs are derived from a Cox proportional hazard regression model adjusted for treatment and are for the proportion of patients with an event with liraglutide vs. placebo.